N-containing heteroaryl derivatives as jak3 kinase inhibitors

ABSTRACT

N-containing heteroaryl derivatives of formula I or II, wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as JAK, particularly JAK3, kinase inhibitors.

FIELD OF THE INVENTION

The present invention relates to a new series of N-containing heteroarylderivative, as well as to processes for their preparation, topharmaceutical compositions comprising them and to their use in therapy.

BACKGROUND OF THE INVENTION

The Janus kinases (JAKs) are cytoplasmic protein tyrosine kinases thatplay pivotal roles in pathways that modulate cellular functions in thelympho-hematopoietic system that are critical for cell proliferation andcell survival. JAKs are involved in the initiation of cytokine-triggeredsignaling events by activating through tyrosine phosphorylation thesignal transducers and activators of transcription (STAT) proteins.JAK/STAT signaling has been implicated in the mediation of many abnormalimmune responses such as transplant rejection and autoimmune diseases,as well as in solid and hematologic malignancies such as leukemias andlymphomas and in myeloproliferative disorders, and has thus emerged asan interesting target for drug intervention.

Four members of the JAK family have been identified so far: JAK1, JAK2,JAK3 and Tyk2. Unlike JAK1, JAK2 and Tyk2, whose expression isubiquitous, JAK3 is mainly found in hematopoietic cells, JAK3 isassociated in a non-covalent manner with the γc subunit of the receptorsof IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15. These cytokines play animportant role in the proliferation and differentiation of Tlymphocytes. JAK3-deficient mouse T cells do not respond to IL-2. Thiscytokine is fundamental in the regulation of T lymphocytes. In thisregard, it is known that antibodies directed against the IL-2 receptorare able to prevent transplant rejection. In patients with X severecombined immunodeficiency (X-SCID), very low levels of JAK3 expressionas well as genetic defects in the γc subunit of the receptor have beenidentified, which indicates that immunosuppression is a consequence ofan alteration in the JAK3 signaling pathway.

Animal studies have suggested that JAK3 not only plays a critical rolein T and B lymphocyte maturation, but also that JAK3 is required tomaintain lymphocyte function. Modulation of the immunological activitythrough this new mechanism can prove useful in the treatment of T cellproliferative disorders such as transplant rejection and autoimmunediseases.

JAK3 has also been shown to play an important role in mast cells,because antigen-induced degranulation and mediator release have beenfound to be substantially reduced in mast cells from JAK3 deficientmice. JAK3 deficiency does not affect mast cell proliferation nor IgEreceptor expression levels. On the other hand, JAK3−/− and JAK3+/+ mastcells contain the same intracellular mediators. Therefore, JAK3 appearsto be essential in the IgE-induced release of mediators in mast cellsand its inhibition would be, thus, an effective treatment for allergicreactions.

In conclusion, JAK3 kinase inhibitors have been recognised as a newclass of effective immunosuppressive agents useful for transplantrejection prevention and in the treatment of immune, autoimmune,inflammatory and proliferative diseases such as psoriasis, psoriaticarthritis, rheumatoid arthritis, multiple sclerosis, inflammatory boweldiseases, systemic lupus erythematosus, type I diabetes andcomplications from diabetes, allergic reactions and leukemia (see e.g.O'Shea J. J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64;Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84;Cetkovic-Cvrlje M. et al, Arch. Immunol. Ther. Exp. (Warsz), 2004,52(2):69-82).

Accordingly, it would be desirable to provide novel compounds that arecapable of inhibiting JAK/STAT signaling pathways, and in particularwhich are capable of inhibiting JAK3 activity, and which are good drugcandidates. Compounds should exhibit good activity in in vitro and invivo pharmacological assays, good oral absorption when administered bythe oral route, as well as be metabolically stable and exhibit afavourable pharmacokinetic profile. Moreover, compounds should not betoxic and exhibit few side effects.

DESCRIPTION OF THE INVENTION

One aspect of the invention relates to a compound of formula I or II

wherein

A is carbon and B is nitrogen, or A is nitrogen and B is carbon;

W is CH or N;

R₁ and R₂ independently are hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN,—OR₈ or —SR₈;

R₃ is C₁₋₄alkyl, R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄-alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hyroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl, R₁₃CONR₇—C₀₋₄alkyl,R₁₃R₇NCO—C₀₋₄alkyl, R₁₂R₇NCONR₇—C₀₋₄alkyl, R₁₃CO₂NR₇—C₀₋₄alkyl,R₁₃SO₂NR₇—C₀₋₄alkyl, —OR₁₂ or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionallysubstituted with one or more R₁₁;

R₅ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —OR₁₂, —NR₇R₁₂, orCy₂-C₀₋₄alkyl, wherein Cy₂ is optionally substituted with one or moreR₁₁;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl, R₁₆CO—O—C₁₋₄alkyl,cyanoC₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionallysubstituted with one or more R₁₁;

R₇ is hydrogen or C₁₋₄alkyl;

R₈ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, orC₁₋₄alkoxyC₁₋₄alkyl;

R₉ is halogen, —CN, —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂, —OR₁₂, —OCONR₇R₁₂,—SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or—NR₇SO₂R₁₃;

R₁₀ is C₁₋₄alkyl or R₉—C₀₋₄alkyl;

R₁₁ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, halogen, —CN, —CONR₇R₁₄, —COR₁₄, —CO₂R₁₅, —OR₁₄,—OCONR₇R₁₄, —SO₂R₁₅, —SO₂NR₇R₁₄, —NR₇R₁₄, —NR₇COR₁₄, —NR₇CONR₇R₁₄,—NR₇CO₂R₁₅ or —NR₇SO₂R₁₅;

R₁₂ is hydrogen or R₁₃;

R₁₃ is C₁₋₅alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, Cy₂-C₀₋₄alkyl or R₁₄R₇N—C₁₋₄alkyl; wherein Cy₂ isoptionally substituted with one or more R₁₁;

R₁₄ is hydrogen or R₁₅;

R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl;

R₁₆ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl or cyanoC₁₋₄alkyl;

Cy₁ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 4 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and

Cy₂ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 4 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C or N atom, and whereinone or more C or S ring atoms are optionally oxidized forming CO, SO orSO₂

The compounds of formula I or II are JAK, particularly JAK3, kinaseinhibitors and therefore can be useful for the treatment or preventionof any disease mediated by JAKs, and particularly JAK3.

Thus, another aspect of the invention relates to a compound of formula Ior II

wherein

A is carbon and B is nitrogen, or A is nitrogen and B is carbon;

W is CH or N;

R₁ and R₂ independently are hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN,—OR₈ or —SR₈;

R₃ is C₁₋₄alkyl, R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl, R₁₃CONR₇—C₀₋₄alkyl,R₁₃R₇NCO—C₀₋₄alkyl, R₁₂R₇NCONR₇—C₀₋₄alkyl, R₁₃CO₂NR₇—C₀₋₄alkyl,R₁₃SO₂NR₇—C₀₋₄alkyl, —OR₁₂ or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionallysubstituted with one or more R₁₁;

R₅ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —OR₁₂, —NR₇R₁₂, orCy₂-C₀₋₄alkyl, wherein Cy₂ is optionally substituted with one or moreR₁₁;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₅CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl, R₁₆CO—O—C₁₋₄alkyl,cyanoC₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ or Cy₂ are optionallysubstituted with one or more R₁₁;

R₇ is hydrogen or C₁₋₄alkyl;

R₈ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, orC₁₋₄alkoxyC₁₋₄alkyl;

R₉ is halogen, —CN, —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂, —OR₁₂, —OCONR₇R₁₂,—SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ orNR₇SO₂R₁₃;

R₁₀ is C₁₋₄alkyl or R₉—C₀₋₄alkyl;

R₁₁ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, halogen, —CN, —CONR₇R₁₄, —COR₁₄, —CO₂R₁₆, —OR₁₄,—OCONR₇R₁₄, —SO₂R₁₅, —SO₂NR₇R₁₄, —NR₇R₁₄, —NR₇COR₁₄, —NR₇CONR₇R₁₄,—NR₇CO₂R₁₅ or —NR₇SO₂R₁₅;

R₁₂ is hydrogen or R₁₃,

R₁₃ is C₁₋₅alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, Cy₂-C₀₋₄alkyl or R₁₄R₇N—C₁₋₄alkyl; wherein Cy₂ isoptionally substituted with one or more R₁₁;

R₁₄ is hydrogen or R₁₅;

R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl;

R₁₆ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl or cyanoC₁₋₄alkyl;

Cy₁ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 4 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and

Cy₂ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 4 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C or N atom, and whereinone or more C or S ring atoms are optionally oxidized forming CO, SO orSO₂; for use in therapy.

Another aspect of the invention relates to a pharmaceutical compositionwhich comprises a compound of formula I or II or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptableexcipients.

Another aspect of the present invention relates to the use of a compoundof formula I or II or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment or prevention of a diseasemediated by JAKs, particularly JAK3. More preferably, the diseasemediated by JAKs, particularly JAK3, is at least one disease selectedfrom transplant rejection, immune, autoimmune or inflammatory diseases,neurodegenerative diseases, or proliferative disorders. In a furtherpreferred embodiment, the disease mediated by JAKs, particularly JAK3,is selected from transplant rejection or immune, autoimmune orinflammatory diseases. In a further preferred embodiment, the diseasemediated by JAKs, particularly JAK3, is a proliferative disorder.

Another aspect of the present invention relates to the use of a compoundof formula I or II or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment or prevention of at leastone disease selected from transplant rejection, immune, autoimmune orinflammatory diseases, neurodegenerative diseases, or proliferativedisorders. In a preferred embodiment, the disease is selected fromtransplant rejection or immune, autoimmune or inflammatory diseases. Ina further preferred embodiment, the disease is a proliferative disorder.

Another aspect of the present invention relates to the use of a compoundof formula I or II or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment or prevention of a diseaseselected from transplant rejection, rheumatoid arthritis, psoriaticarthritis, psoriasis, type I diabetes, complications from diabetes,multiple sclerosis, systemic lupus erythematosus, atopic dermatitis,mast cell-mediated allergic reactions, inflammatory or autoimmune oculardiseases, leukemias, lymphomas, and thromboembolic and allergiccomplications associated with leukemias and lymphomas.

Another aspect of the present invention relates to a compound of formulaI or II or a pharmaceutically acceptable salt thereof for use in thetreatment or prevention of a disease mediated by JAKs, particularlyJAK3. More preferably, the disease mediated by JAKs, particularly JAK3,is at least one disease selected from transplant rejection, immune,autoimmune or inflammatory diseases, neurodegenerative diseases, orproliferative disorders. In a further preferred embodiment, the diseasemediated by JAKs, particularly JAK3, is selected from transplantrejection or immune, autoimmune or inflammatory diseases. In a furtherpreferred embodiment, the disease mediated by JAKs, particularly JAK3,is a proliferative disorder.

Another aspect of the present invention relates to a compound of formulaI or II or a pharmaceutically acceptable salt thereof for use in thetreatment or prevention of at least one disease selected from transplantrejection, immune, autoimmune or inflammatory diseases,neurodegenerative diseases, or proliferative disorders. In a preferredembodiment, the disease is selected from transplant rejection or immune,autoimmune or inflammatory diseases. In a further preferred embodiment,the disease is a proliferative disorder.

Another aspect of the present invention relates to a compound of formulaI or II or a pharmaceutically acceptable salt thereof for use in thetreatment or prevention of a disease selected from transplant rejection,rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes,complications from diabetes, multiple sclerosis, systemic lupuserythematosus, atopic dermatitis, mast cell-mediated allergic reactions,inflammatory or autoimmune ocular diseases, leukemias, lymphomas, andthromboembolic and allergic complications associated with leukemias andlymphomas.

Another aspect of the present invention relates to the use of a compoundof formula I or II or a pharmaceutically acceptable salt thereof for thetreatment or prevention of a disease mediated by JAKs, particularlyJAK3. More preferably, the disease mediated by JAKs, particularly JAK3,is at least one disease selected from transplant rejection, immune,autoimmune or inflammatory diseases, neurodegenerative diseases, orproliferative disorders. In a further preferred embodiment, the diseasemediated by JAKs, particularly JAK3, is selected from transplantrejection or immune, autoimmune or inflammatory diseases. In a furtherpreferred embodiment, the disease mediated by JAKs, particularly JAK3,is a proliferative disorder.

Another aspect of the present invention relates to the use of a compoundof formula I or II or a pharmaceutically acceptable salt thereof for thetreatment or prevention of at least one disease selected from transplantrejection, immune, autoimmune or inflammatory diseases,neurodegenerative diseases, or proliferative disorders. In a preferredembodiment, the disease is selected from transplant rejection or immune,autoimmune or inflammatory diseases. In a further preferred embodiment,the disease is a proliferative disorder.

Another aspect of the present invention relates to the use of a compoundof formula I or II or a pharmaceutically acceptable salt thereof for thetreatment or prevention of a disease selected from transplant rejection,rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes,complications from diabetes, multiple sclerosis, systemic lupuserythematosus, atopic dermatitis, mast cell-mediated allergic reactions,inflammatory or autoimmune ocular diseases, leukemias, lymphomas, andthromboembolic and allergic complications associated with leukemias andlymphomas.

Another aspect of the present invention relates to a method of treatingor preventing a disease mediated by JAKs, particularly JAK3, in asubject in need thereof, especially a human being, which comprisesadministering to said subject an amount of a compound of formula I or IIor a pharmaceutically acceptable salt thereof effective to treat saiddisease. More preferably, the disease mediated by JAKs, particularlyJAK3, is at least one disease selected from transplant rejection,immune, autoimmune or inflammatory diseases, neurodegenerative diseases,or proliferative disorders. In a further preferred embodiment, thedisease mediated by JAKs, particularly JAK3, is selected from transplantrejection or immune, autoimmune or inflammatory diseases. In a furtherpreferred embodiment, the disease mediated by JAKs, particularly JAK3,is a proliferative disorder.

Another aspect of the present invention relates to a method of treatingor preventing at least one disease selected from transplant rejection,immune, autoimmune or inflammatory diseases, neurodegenerative diseases,or proliferative disorders in a subject in need thereof, especially ahuman being, which comprises administering to said subject an amount ofa compound of formula I or II or a pharmaceutically acceptable saltthereof effective to treat said disease. In a preferred embodiment, thedisease is selected from transplant rejection or immune, autoimmune orinflammatory diseases. In a further preferred embodiment, the disease isa proliferative disorder.

Another aspect of the present invention relates to a method of treatingor preventing a disease selected from transplant rejection, rheumatoidarthritis, psoriatic arthritis, psoriasis, type I diabetes,complications from diabetes, multiple sclerosis, systemic lupuserythematosus, atopic dermatitis, mast cell-mediated allergic reactions,inflammatory or autoimmune ocular diseases, leukemias, lymphomas, andthromboembolic and allergic complications associated with leukemias andlymphomas in a subject in need thereof, especially a human being, whichcomprises administering to said subject an amount of a compound offormula I or II or a pharmaceutically acceptable salt thereof effectiveto treat said disease.

Another aspect of the present invention relates to a process for thepreparation of a compound of formula I or II as defined above, whichcomprises:

(a) for a compound of formula I, reacting a compound of formula VI witha compound of formula III

wherein A, B, W, R₁, R₂, R₃, R₄ and R₅ have the meaning previouslydescribed in relation with a compound of formula I or II; or

(b) for a compound of formula I, reacting a compound of formula VI witha compound of formula IV

wherein A, B, W, R₁, R₂, R₃, R₄ and R₅ have the meaning previouslydescribed in relation with a compound of formula I or II; or

(c) when in a compound of formula II R₅ is hydrogen (a compound offormula IIa), reacting a compound of formula VI, as defined above, witha synthetic equivalent for the CO synthon.

wherein A, B, W, R₁, R₂, R₃ and R₅ have the meaning previously describedin relation with a compound of formula I or II; or

(d) when in a compound of formula II R₆ is other than hydrogen, reactinga compound of formula IIa with a compound of formula V (R₆-X) in thepresence of a base, wherein X is a leaving group; or

(e) converting, in one or a plurality of steps, a compound of formula Ior II into another compound of formula I or II.

In the above definitions, the term C₁₋₅ alkyl, as a group or part of agroup, means a straight or branched alkyl chain which contains from 1 to5 carbon atoms and includes among others the groups methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl andiso-pentyl. Likewise, the term C₁₋₄alkyl, as a group or part of a group,means a straight or branched alkyl chain which contains from 1 to 4carbon atoms and includes the groups methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl and tert-butyl.

A C₁₋₄alkoxy group, as a group or part of a group, means a group offormula —OC₁₋₄alkyl, wherein the C₁₋₄alkyl moiety has the same meaningas previously described. Examples include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

A C₁₋₄alkoxyC₁₋₄alkyl group means a group resulting from the replacementof one or more hydrogen atoms from a C₁₋₄alkyl group with one or moreC₁₋₄alkoxy groups as defined above, which can be the same or different.Examples include, among others, the groups methoxymethyl, ethoxymethyl,propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl,sec-butoxymethyl, tert-butoxymethyl, dimethoxymethyl, 1-methoxyethyl,2-methoxyethyl, 2-ethoxyethyl, 1,2-diethoxyethyl, 1-butoxyethyl,2-sec-butoxyethyl, 3-methoxypropyl, 2-butoxypropyl,1-methoxy-2-ethoxypropyl, 3-tert-butoxypropyl and 4-methoxybutyl.

Halogen or its abbreviation halo means fluoro, chloro, bromo or iodo.

A haloC₁₋₄alkyl group means a group resulting from the replacement ofone or more hydrogen atoms from a C₁₋₄alkyl group with one or morehalogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be thesame or different. Examples include, among others, the groupstrifluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl,1-fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl,2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl,2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl,heptafluoropropyl, 4-fluorobutyl, nonafluorobutyl,1-chloro-2-fluoroethyl and 2-bromo-1-chloro-1-fluoropropyl.

A hydroxyC₁₋₄alkyl group means a group resulting from the replacement ofone or more hydrogen atoms from a C₁₋₄alkyl group with one or morehydroxy groups. Examples include, among others, the groupshydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2,3-dihydroxypropyl,4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl and 1-hydroxybutyl.

A cyanoC₁₋₄alkyl group means a group resulting from the replacement ofone or more hydrogen atoms from a C₁₋₄alkyl group with one or more cyanogroups. Examples include, among others, the groups cyanomethyl,dicyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl,2,3-dicyanopropyl and 4-cyanobutyl.

A haloC₁₋₄alkoxy group means a group resulting from the replacement ofone or more hydrogen atoms from a C₁₋₄ alkoxy group with one or morehalogen atoms (i.e. fluoro, chloro, bromo or iodo) which can be the sameor different. Examples include, among others, the groupstrifluoromethoxy, fluoromethoxy, 1-chloroethoxy, 2-chloroethoxy,1-fluoroethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2-iodoethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy,3-chloropropoxy, 2,2,3,3-tetrafluoropropoxy,2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4-fluorobutoxy,nonafluorobutoxy, 1-chloro-2-fluoroethoxy and2-bromo-1-chloro-1-fluoropropoxy.

The term C₀ alkyl indicates that the alkyl group is absent.

Thus, the term R₉—C₀₋₄alkyl includes R₉ and R₉—C₁₋₄ alkyl. The termR₉—C₁₋₄ alkyl relates to a group resulting from the substitution of onehydrogen atom of a C₁₋₄alkyl group with one R₉ group.

The terms R₁₂R₇N—C₀₋₄alkyl, R₁₃CONR₇—C₀₋₄alkyl, R₁₃R₇NCO—C₀₋₄alkyl,R₁₂R₇NCONR₇—C₀₋₄alkyl, R₁₃CO₂NR₇—C₀₋₄alkyl, R₁₃SO₂NR₇—C₀₋₄alkyl,R₁₆CO—C₀₋₄alkyl and R₁₆CO₂—C₀₋₄alkyl include —NR₇R₁₂ andR₁₂R₇N—C₁₋₄alkyl, —NR₇COR₁₃ and R₁₃CONR₇—C₁₋₄alkyl, —CONR₇R₁₃ andR₁₃R₇NCO—C₁₋₄alkyl, —NR₇CONR₇R₁₂ and R₁₂R₇NCONR₇—C₁₋₄alkyl, —NR₇CO₂R₁₃and R₁₃CO₂NR₇—C₁₋₄alkyl, —NR₇SO₂R₁₃ and R₁₃SO₂NR₇—C₁₋₄alkyl, —COR₁₆ andR₁₆CO—C₁₋₄alkyl, and —CO₂R₁₆ and R₁₆CO₂—C₁₋₄alkyl, respectively.

A group R₁₂R₇N—C₁₋₄alkyl, R₁₄R₇N—C₁₋₄alkyl, R₁₃CONR₇—C₁₋₄alkyl,R₁₃R₇NCO—C₁₋₄alkyl, R₁₂R₇NCONR₇—C₁₋₄alkyl, R₁₃CO₂NR₇—C₁₋₄alkyl,R₁₃SO₂NR₇—C₁₋₄alkyl, R₁₆CO—C₁₋₄alkyl, R₁₆CO₂—C₁₋₄alkyl orR₁₆CO—O—C₁₋₄alkyl means a group resulting from the replacement of onehydrogen atom from a C₁₋₄alkyl group with one —NR₇R₁₂, —NR₇R₁₄,—NR₇COR₁₃, —CONR₇R₁₃, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ —NR₇SO₂R₁₃, —COR₁₆,—CO₂R₁₆ or —OCOR₁₆ group, respectively.

A Cy₁ group refers to a 3- to 7-membered monocyclic or 6- to 11-memberedbicyclic carbocyclic or heterocyclic ring, which is saturated, partiallyunsaturated or aromatic. When heterocyclic, it contains from 1 to 4heteroatoms independently selected from N, S and O. Bicyclic rings areformed either by two rings fused through two adjacent C or N atoms, orthrough two non-adjacent C or N atoms forming a bridged ring, or elsethey are formed by two rings bonded through a single common C atomforming a spiro ring. Cy₁ is bonded to the rest of the molecule throughany available C atom. When Cy₁ is saturated or partially unsaturated,one or more C or S atoms of said ring are optionally oxidized formingCO, SO or SO₂ groups. Cy₁ is optionally substituted as disclosed abovein the definition of a compound of formula I or II, said substituentscan be the same or different and can be placed on any available positionof the ring system.

A Cy₂ group refers to a 3- to 7-membered monocyclic or 6- to 11-memberedbicyclic carbocyclic or heterocyclic ring, which is saturated, partiallyunsaturated or aromatic. When heterocyclic, it contains from 1 to 4heteroatoms independently selected from N, S and O. Bicyclic rings areformed either by two rings fused through two adjacent C or N atoms, orthrough two non-adjacent C or N atoms forming a bridged ring, or elsethey are formed by two rings bonded through a single common C atomforming a spiro ring. Cy₂ is bonded to the rest of the molecule throughany available C or N atom. When Cy₂ is saturated or partiallyunsaturated, one or more C or S atoms of said ring are optionallyoxidized forming CO, SO or SO₂ groups. Cy₂ is optionally substituted asdisclosed above in the definition of a compound of formula I or II, saidsubstituents can be the same or different and can be placed on anyavailable position of the ring system.

Examples of either Cy₁ or Cy₂ include, among others, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl,aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl,thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl,1,1-dioxothiomorpholinyl, piperazinyl, homopiperazinyl, piperidinyl,pyranyl, tetrahydropyranyl, homopiperidinyl, oxazinyl, oxazolinyl,pyrrolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, isoxazolinyl,isothiazolinyl 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 4-oxo-piperidinyl,2-oxo-piperazinyl, 2-oxo-1,2-dihydropyridinyl,2-oxo-1,2-dihydropyrazinyl, 2-oxo-1,2-dihydropyrimidinyl,3-oxo-2,3-dihydropyridazyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-oxadiazolyl,1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzooxazolyl,benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl,benzothiazolyl, quinolinyl, isoquinolinyl, phtalazinyl, quinazolinyl,quinoxalinyl, cinolinyl, naphthyridinyl, indazolyl, imidazopyridinyl,pyrrolopyridinyl, thienopyridinyl, imidazopyrimidinyl, imidazopyrazinyl,imidazopyridazinyl, pyrazolopyrazinyl, pyrazolopyridinyl,pyrazolopyrimidinyl, benzo[1,3]dioxolyl, phtalimidyl,1-oxo-1,3-dihydroisobenzofuranyl, 1,3-dioxo-1,3-dihydroisobenzofuranyl,2-oxo-2,3-dihydro-1H-indolyl, 1-oxo-2,3-dihydro-1H-isoindolyl,chromanyl, perhydroquinolinyl, 1-oxo-perhydroisoquinolinyl,1-oxo-1,2-dihydroisoquinolinyl, 4-oxo-3,4-dihydroquinazolinyl,2-aza-bicyclo[2.2.1]heptanyl, 5-aza-bicyclo[2.1.1]hexanyl,2H-spiro[benzofuran-3,4′-piperidinyl],3H-spiro[isobenzofuran-1,4′-piperidinyl],1-oxo-2,8-diazaspiro[4.5]decanyl and 1-oxo-2,7-diazaspiro[4.5]decanyl.

When in the definitions used throughout the present specification forcyclic groups the examples given refer to a radical of a ring in generalterms, for example piperidinyl, tetrahydropyranyl or indolyl, all theavailable bonding positions are included, unless a limitation isindicated in the corresponding definition for said cyclic group, forexample that the ring is bonded through a C atom in Cy₁, in which casesuch limitation applies. Thus for example, in the definitions of Cy₂,which do not include any limitation regarding the bonding position, theterm piperidinyl includes 1-piperidinyl, 2-piperidinyl, 3-piperidinyland 4-piperidinyl; tetrahydropyranyl includes 2-tetrahydropyranyl,3-tetrahydropyranyl and 4-tetrahydropyranyl; and indolyl includes1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl and7-indolyl.

In the above definitions of Cy₁ and Cy₂, when the examples listed referto a bicycle in general terms, all possible dispositions of the atomsare included. Thus, for example, the term pyrazolopyridinyl includesgroups such as 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[1,5-a]pyridinyl,1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl and1H-pyrazolo[4,3-b]pyridinyl, the term imidazopyrazinyl includes groupssuch as 1H-imidazo[4,5-b]pyrazinyl, imidazo[1,2-a]pyrazinyl andimidazo[1,5-a]pyrazinyl and the term pyrazolopyrimidinyl includes groupssuch as 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[4,3-d]pyrimidinyl,pyrazolo[1,5-a]pyrimidinyl and pyrazolo[1,5-c]pyrimidinyl.

The term Cy₂-C₀₋₄alkyl includes Cy₂ and Cy₂-C₁₋₄alkyl.

A Cy₂-C₁₋₄alkyl group means a group resulting from the replacement ofone hydrogen atom from a C₁₋₄alkyl group with one Cy₂ group. Examplesinclude, among others, the groups (piperidinyl-4-yl)methyl,2-(piperidinyl-4-yl)ethyl, 3-(piperidinyl-4-yl)propyl,4-(piperidinyl-4-yl)butyl, (tetrahydropyran-4-yl)methyl,2-(tetrahydropyran-4-yl)ethyl, 3-(tetrahydropyran-4-yl)propyl,4-(tetrahydropyran-4-yl)butyl, benzyl, phenethyl, 3-phenylpropyl,4-phenylbutyl, (indolinyl-1-yl)methyl, 2-(indolinyl-1-yl)ethyl,3-(indolinyl-1-yl)propyl and 4-(indolinyl-1-yl)butyl.

In the definition of a compound of formula I or II, either A is carbonand B is nitrogen, or A is nitrogen and B is carbon. Thus, the compoundsof formula I or II include the following types of compounds:

The expression “optionally substituted with one or more” means that agroup can be substituted with one or more, preferably with 1, 2, 3 or 4substituents, more preferably with 1, 2 or 3 substituents, and stillmore preferably with 1 or 2 substituents, provided that said group hasenough positions susceptible of being substituted. The substituents canbe the same or different and are placed on any available position.

In certain embodiments of Cy₁ mentioned below, a nitrogen atom that canbe substituted means a nitrogen atom that has a hydrogen substituent.

Throughout the present specification, by the term “treatment” is meanteliminating, reducing or ameliorating the cause or the effects of adisease. For purposes of this invention treatment includes, but is notlimited to, alleviation, amelioration or elimination of one or moresymptoms of the disease; diminishment of the extent of the disease;stabilized (i.e. not worsening) state of disease; delay or slowing ofdisease progression; amelioration or palliation of the disease state;and remission of the disease (whether partial or total).

As used herein, “prevention” refers to preventing the occurrence of adisease in a subject that is predisposed to or has risk factors but doesnot yet display symptoms of the disease. Prevention includes alsopreventing the recurrence of a disease in a subject that has previouslysuffered said disease.

Any formula given herein is intended to represent unlabeled forms aswell as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labelled compoundsare useful in metabolic studies (preferably with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly preferredfor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of the invention can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent. In addition to theunlabeled form, all isotopically labeled forms of the compounds offormula I and II are included within the scope of the invention.

Any formula given herein is also intended to represent the correspondingtautomers forms. “Tautomer” refers to alternate forms of a molecule thatdiffer in the position of a proton. Examples include, among others,enol-keto and imine-enamine tautomers, and the tautomeric forms ofheteroaryl groups containing a —N═CH—NH— ring atom arrangement, such aspyrazoles, imidazoles, benzimidazoles, triazoles and tetrazoles.

The invention thus relates to the compounds of formula I or II asdefined above.

In another embodiment, the invention relates to a compound of formula Ior II

wherein

A is carbon and B is nitrogen, or A is nitrogen and B is carbon;

W is CH or N;

R₁ and R₂ independently are hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN,—OR₈ or —SR₈;

R₃ is C₁₋₄alkyl, R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl, R₁₃CONR₇—C₀₋₄alkyl,R₁₃R₇NCO—C₀₋₄alkyl, R₁₂R₇NCONR₇—C₀₋₄alkyl, R₁₃CO₂NR₇—C₀₋₄alkyl,R₁₃SO₂NR₇—C₀₋₄alkyl, —OR₁₂ or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionallysubstituted with one or more R₁₁;

R₅ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —OR₁₂, —NR₇R₁₂, orCy₂-C₀₋₄alkyl, wherein Cy₂ is optionally substituted with one or moreR₁₁;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₁;

R₇ is hydrogen or C₁₋₄alkyl;

R₈ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, orC₁₋₄alkoxyC₁₋₄alkyl;

R₉ is halogen, —CN, —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂, —OR₁₂, —OCONR₇R₁₂,—SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂ —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or—NR₇SO₂R₁₃;

R₁₀ is C₁₋₄alkyl or R₉—C₀₋₄alkyl;

R₁₁ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, halogen, —CN, —CONR₇R₁₄, —COR₁₄, —CO₂R₁₅, —OR₁₄,—OCONR₇R₁₄, —SO₂R₁₅, —SO₂NR₇R₁₄, —NR₇R₁₄, —NR₇R₁₄, —NR₇CONR₇R₁₄,—NR₇CO₂R₁₅ or —NR₇SO₂R₁₅;

R₁₂ is hydrogen or R₁₃.

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionally substitutedwith one or more R₁₁;

R₁₄ is hydrogen or R₁₅;

R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl;

Cy₁ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 4 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and

Cy₂ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 4 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C or N atom, and whereinone or more C or S ring atoms are optionally oxidized forming CO, SO orSO₂.

In another embodiment, the invention relates to a compound of formula Ior II

wherein

A is carbon and B is nitrogen, or A is nitrogen and B is carbon;

W is CH or N;

R₁ and R₂ independently are hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl,hydroxyC₁₋₄alky, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈or SR₈;

R₃ is C₁₋₄alkyl, R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂are optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₃CONR₇—C₀₋₄alkyl,R₁₃R₇NCO—C₀₋₄alkyl, R₁₂R₇NCONR₇—C₀₋₄alkyl, R₁₃CO₂NR₇—C₀₋₄alkyl,R₁₃SO₂NR₇—C₀₋₄alkyl, —OR₁₂ or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionallysubstituted with one or more R₁₁;

R₅ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —OR₁₂, —NR₇R₁₂, orCy₂-C₀₋₄alkyl, wherein Cy₂ is optionally substituted with one or moreR₁₁;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl, Cy₁ orCy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with oneor more R₁₁;

R₇ is hydrogen or C₁₋₄alkyl;

R₈ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, orC₁₋₄alkoxyC₁₋₄alkyl;

R₉ is halogen, —CN, —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂, —OR₁₂, —OCONR₇R₁₂,—SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or—NR₇SO₂R₁₃;

R₁₀ is C₁₋₄alkyl or R₉—C₀₋₄alkyl;

R₁₁ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, halogen, —CN, —CONR₇R₁₄, —COR₁₄, —CO₂R₁₅, —OR₁₄,—OCONR₇R₁₄, —SO₂R₁₅, —SO₂NR₇R₁₄, —NR₇R₁₄, —NR₇COR₁₄, —NR₇CONR₇R₁₄,—NR₇CO₂R₁₅ or —NR₇SO₂R₁₅;

R₁₂ is hydrogen or R₁₃.

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, or Cy₂-C₀₋₄alkyl; wherein Cy₂ is optionally substitutedwith one or more R₁₁;

R₁₄ is hydrogen or R₁₅;

R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl;

R₁₆ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl or cyanoC₁₋₄alkyl;

Cy₁ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 4 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and

Cy₂ is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 4 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C or N atom, and whereinone or more C or S ring atoms are optionally oxidized forming CO, SO orSO₂.

In another embodiment, the invention relates to the compounds of formulaI.

In another embodiment, the invention relates to the compounds of formulaII.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is carbon and B is nitrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon.

In another embodiment, the invention relates to the compounds of formulaI or II wherein W is CH.

In another embodiment, the invention relates to the compounds of formulaI or II wherein W is N.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁ and R₂ independently are hydrogen, halogen, —CN, —OR₈or —SR₈, preferably hydrogen or —CN.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₂ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₂ is —CN.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, morepreferably hydrogen or —CN; and R₂ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁ is hydrogen or —CN.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁ is hydrogen; and R₂ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁ is —CN; and R₂ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁and Cy₂ are optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is R₉—C₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is Cy₁, which is optionally substituted with one ormore R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is Cy₁ and Cy₁ is a 3- to 7-membered monocyclic or 6-to 11-membered bicyclic ring, which is saturated, partially unsaturatedor aromatic, and which is carbocyclic or heterocyclic containing from 1to 4 heteroatoms independently selected from N, S and O, wherein saidring is bonded to the rest of the molecule through any available C atom,and wherein one or more C or S ring atoms are optionally oxidizedforming CO, SO or SO₂; wherein said Cy₁ is optionally substituted withone or more R₁₀ provided that if the ring contains a nitrogen atom thatcan be substituted, then said nitrogen atom is substituted with one R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is Cy₁; and Cy₁ in R₃ is a 3- to 7-memberedmonocyclic ring, which is saturated, partially unsaturated or aromatic,and which is carbocyclic or heterocyclic containing from 1 to 3heteroatoms independently selected from N, S and O, wherein said ring isbonded to the rest of the molecule through any available C atom, andwherein one or more C or S ring atoms are optionally oxidized formingCO, SO or SO₂; and wherein said Cy₁ is optionally substituted with oneor more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is Cy₁; and Cy₁ in R₃ is a 3- to 7-membered saturatedmonocyclic ring, which is carbocyclic or heterocyclic containing from 1to 3 heteroatoms independently selected from N, S and O, wherein saidring is bonded to the rest of the molecule through any available C atom,and wherein one or more C or S ring atoms are optionally oxidizedforming CO, SO or SO₂; and wherein said Cy₁ is optionally substitutedwith one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is Cy₁; and Cy₁ in R₃ is a 5- to 6-membered saturatedmonocyclic ring, which is carbocyclic or heterocyclic containing from 1to 3 heteroatoms independently selected from N, S and O, wherein saidring is bonded to the rest of the molecule through any available C atom,and wherein one or more C or S ring atoms are optionally oxidizedforming CO, SO or SO₂; and wherein said Cy₁ is optionally substitutedwith one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is Cy₁; and Cy₁ in R₃ is a 5- to 6-membered saturatedmonocyclic ring, which is carbocyclic or heterocyclic containing from 1to 3 heteroatoms independently selected from N, S and O, at least one ofwhich is N; wherein said ring is bonded to the rest of the moleculethrough any available C atom, and wherein one or more C or S ring atomsare optionally oxidized forming CO, SO or SO₂; and wherein said Cy₁ isoptionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is Cy₁; and Cy₁ in R₃ is a 3- to 7-membered,preferably 5- to 6-membered saturated monocyclic ring, which isheterocyclic containing from 1 to 3 heteroatoms independently selectedfrom N, S and O, at least one of which is N; wherein said ring is bondedto the rest of the molecule through any available C atom, and whereinone or more C or S ring atoms are optionally oxidized forming CO, SO orSO₂; and wherein said Cy₁ is optionally substituted with one or moreR₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is piperidinyl or pyrrolidinyl, preferablypiperidin-3-yl or pyrrolidin-3-yl, which are optionally substituted withone or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is piperidinyl or pyrrolidinyl, preferablypiperidin-3-yl or pyrrolidin-3-yl, which are substituted with one R₁₀ onthe N atom of the piperidinyl or pyrrolidinyl ring and which areoptionally further substituted with one or more R₁₀ groups.

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is piperidinyl or pyrrolidinyl, preferably piperidin-3-ylor pyrrolidin-3-yl, which are optionally substituted with one or moreR₁₀.

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is piperidinyl or pyrrolidinyl, preferably piperidin-3-ylor pyrrolidin-3-yl, which are substituted with one R₁₀ on the N atom ofthe piperidinyl or pyrrolidinyl ring and which are optionally furthersubstituted with one or more R₁₀ groups.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is piperidinyl, preferably piperidin-3-yl, which areoptionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is piperidinyl, preferably piperidin-3-yl,substituted with one R₁₀ on the N atom of the piperidinyl ring andoptionally further substituted with one or more R₁₀ groups.

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is piperidinyl, preferably piperidin-3-yl, which areoptionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is piperidinyl, preferably piperidin-3-yl, substitutedwith one R₁₀ on the N atom of the piperidinyl ring and optionallyfurther substituted with one or more R₁₀ groups.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is a cycle of formula

wherein Cy_(1a) and Cy_(1b) are optionally substituted with one or morefurther R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is a cycle of formula

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is a cycle of formula

wherein Cy_(1a) and Cy_(1b) are optionally substituted with one or morefurther R₁₀.

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is a cycle of formula

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is a cycle of formula Cy_(1a).

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is a cycle of formula Cy_(1a).

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is a cycle of formula

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is a cycle of formula

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is a cycle of formula Cy_(1a) and Cy_(1a) has the(S)-stereochemistry.

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is a cycle of formula Cy_(1a) and Cy_(1a) has the(S)-stereochemistry.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is a cycle of formula Cy_(1b).

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is Cy₂-C₁₋₄alkyl, wherein Cy₂ is optionallysubstituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is Cy₂-C₁₋₄alkyl; and Cy₂ is a 3- to 7-memberedmonocyclic ring, which is saturated, partially unsaturated or aromatic,and which is carbocyclic or heterocyclic containing from 1 to 3heteroatoms independently selected from N, S and O, wherein said ring isbonded to the rest of the molecule through any available C o N atom, andwherein one or more C or S ring atoms are optionally oxidized formingCO, SO or SO₂; and wherein said Cy₂ is optionally substituted with oneor more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl orCy₂-C₀₋₄alkyl, preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; whereinCy₂ is optionally substituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₅ is hydrogen or Cy₂; wherein Cy₂ is optionallysubstituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₅ is hydrogen or Cy₂; and Cy₂ is a 3- to 7-memberedmonocyclic ring, which is saturated, partially unsaturated or aromatic,and which is carbocyclic or heterocyclic containing from 1 to 3heteroatoms independently selected from N, S and O, wherein said ring isbonded to the rest of the molecule through any available C o N atom, andwherein one or more C or S ring atoms are optionally oxidized formingCO, SO or SO₂; and wherein said Cy₂ is optionally substituted with oneor more R₁₁.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₆ is C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl, R₁₆CO—O—C₁₋₄alkyl,cyanoC₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionallysubstituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl,Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substitutedwith one or more R₁₁.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₆ is C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl, Cy₁ orCy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with oneor more R₁₁.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₆ is C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl orR₁₆CO—O—C₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₆ is C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl or R₁₂R₇N—C₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₆ is hydrogen or C₁₋₄alkyl, preferably hydrogen, methylor ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₆ is C₁₋₄alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein R₆ is C₁₋₄alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein R₆ methyl.

In another embodiment, the invention relates to the compounds of formulaII wherein R₆ is ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₉ is —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂, —OR₁₂, —OCONR₇R₁₂,—SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or—NR₇SO₂R₁₃, preferably R₉ is —COR₁₃.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁₀ is R₉—C₀₋₄alkyl, preferably R₉.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁₀ is R₉; and R₉ in R₁₀ is —COR₁₃ or —SO₂R₁₃. Inanother embodiment, the invention relates to the compounds of formula Ior II wherein R₁₀ is R₉; and R₉ in R₁₀ is —COR₁₃.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl or Cy₂-C₀₋₄alkyl; wherein Cy₂ isoptionally substituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁₃ is C₁₋₅alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl orcyanoC₁₋₄alkyl, more preferably methyl, isopropyl or cyanomethyl, andstill more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl orcyanoC₁₋₄alkyl, more preferably methyl, isopropyl or cyanomethyl, andstill more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁₃ is methyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁₃ is isopropyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁₃ is cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁₃ is Cy₂-C₀₋₄alkyl wherein Cy₂ is optionallysubstituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₉ is —CONR₇R₁₂, —COR₁₃, —CO₂R₁₃, —OR₁₂, —OCONR₇R₁₂,—SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or—NR₇SO₂R₁₃, preferably —CO₂R₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁₀ is R₉; R₉ in R₁₀ is —COR₁₃; and R₁₃ is C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl or cyanoC₁₋₄alkyl,preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and more preferably methyl orcyanomethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is R₉—C₁₋₄alkyl; and

R₉ is —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂, —OR₁₂, —OCONR₇R₁₂, —SO₂R₁₃,—SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂ —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or —NR₇SO₂R₁₃.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is R₉—C₁₋₄alkyl;

R₉ is —CONR₇R₁₂, —COR₁₃, —CO₂R₁₃, —OR₁₂, —OCONR₇R₁₂, —SO₂R₁₃,—SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂, —NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or —NR₇SO₂R₁₃;and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is Cy₁, preferably piperidinyl or pyrrolidinyl, morepreferably piperidinyl-3-yl or pyrrolidinyl-3-yl; wherein Cy₁ in R₃ isoptionally substituted with one or more R₁₀; and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is a cycle of formula

and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃.

In another embodiment, the invention relates to the compounds or formulaII wherein R₃ is a cycle of formula

and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃.

In another embodiment the invention relates to the compounds of formulaI or II wherein R₃ is a cycle of formula

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉;

R₉ is —COR₁₃ or —SO₂R₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is a cycle of formula

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉;

R₉ is —COR₁₃ or —SO₂R₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is a cycle of formula Cy_(1a); and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃still more preferably —COR₁₃.

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is a cycle of formula Cy_(1a); and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃still more preferably —COR₁₃.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is a cycle of formula Cy_(1a);

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃,still more preferably —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is a cycle of formula Cy_(1a);

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃,still more preferably —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is a cycle of formula Cy_(1a) with(S)-stereochemistry;

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or—SO₂R₁₃still more preferably —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is a cycle of formula Cy_(1a) with (S)-stereochemistry;

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —COR₁₃ or —SO₂R₁₃,still more preferably —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₃ is a cycle of formula Cy_(1b); and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —SO₂R₁₃.

In another embodiment, the invention relates to the compounds of formulaII wherein R₃ is a cycle of formula Cy_(1b); and

R₁₀ is R₉—C₀₋₄alkyl, preferably R₉, more preferably —SO₂R₁₃.

In another embodiment, the invention relates to the compounds of formulaI or II wherein Cy₁ is a 3- to 7-membered monocyclic ring, which issaturated, partially unsaturated or aromatic, and which is carbocyclicor heterocyclic containing from 1 to 3 heteroatoms independentlyselected from N, S and O, wherein said ring is bonded to the rest of themolecule through any available C atom, and wherein one or more C or Sring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formulaI or II wherein Cy₁ is a 3- to 7-membered saturated monocyclic ring,which is carbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formulaI or II wherein Cy₁ is a 5- to 6-membered saturated monocyclic ring,which is carbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formulaI or II wherein Cy₁ is a 5- to 6-membered saturated monocyclic ring,which is carbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, at least one of which is N;wherein said ring is bonded to the rest of the molecule through anyavailable C atom, and wherein one or more C or S ring atoms areoptionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formulaI or II wherein Cy₁ is a 5- to 6-membered saturated monocyclic ring,which is heterocyclic containing from 1 to 3 heteroatoms independentlyselected from N, S and O, at least one of which is N; wherein said ringis bonded to the rest of the molecule through any available C atom, andwherein one or more C or S ring atoms are optionally oxidized formingCO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formulaI or II wherein Cy₁ is piperidinyl or pyrrolidinyl, preferablypiperidinyl-3-yl or pyrrolidinyl-3-yl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein Cy₂ is a 3- to 7-membered monocyclic ring, which issaturated, partially unsaturated or aromatic, and which is carbocyclicor heterocyclic containing from 1 to 3 heteroatoms independentlyselected from N, S and O, wherein said ring is bonded to the rest of themolecule through any available C o N atom, and wherein one or more C orS ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formulaI or II wherein Cy₂ is a 3- to 7-membered saturated monocyclic ring,which is carbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formulaI or II wherein Cy₂ is a 5- to 6-membered saturated monocyclic ring,which is carbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formulaI or II wherein Cy₂ is a 5- to 6-membered saturated monocyclic ring,which is carbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, at least one of which is N;wherein said ring is bonded to the rest of the molecule through anyavailable C atom, and wherein one or more C or S ring atoms areoptionally oxidized forming CO, SO or SO₂.

In another embodiment, the invention relates to the compounds of formulaI or II wherein Cy₂ is piperidinyl or pyrrolidinyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon; and

R₁ and R₂ independently are hydrogen, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen or —CN.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferablyhydrogen or —CN; and

R₂ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon; R₁ and R₂ are hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ and R₂ independently are hydrogen, halogen, —CN, —OR₈ or —SR₈, andmore preferably hydrogen or —CN; and

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferablyhydrogen or —CN;

R₂ is hydrogen; and

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁ and R₂ are hydrogen; and R₃ is R₉—C₁₋₄alkyl, Cy₁ orCy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with oneor more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferablyhydrogen or —CN;

R₂ is hydrogen; and

R₃ is R₉—C₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferablyhydrogen or —CN;

R₂ is hydrogen; and

R₃ is Cy₁, which is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁ and R₂ are hydrogen; and R₂ is Cy₁, which isoptionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferablyhydrogen or —CN;

R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and wherein said Cy₁ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferablyhydrogen or —CN;

R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to8-membered, saturated monocyclic ring, which is carbocyclic orheterocyclic containing from 1 to 3 heteroatoms independently selectedfrom N, S and O, wherein said ring is bonded to the rest of the moleculethrough any available C atom, and wherein one or more C or S ring atomsare optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁in R₃ is piperidinyl or pyrrolidinyl, even more preferablypiperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionallysubstituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferablyhydrogen or —CN;

R₂ is hydrogen; and

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon; R₁ and R₂ are hydrogen;and R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferablyhydrogen or —CN;

R₂ is hydrogen; and

R₃ is R₉—C₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon; R₁ and R₂ are hydrogen;and R₃ is R₉—C₁₋₄alkyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferablyhydrogen or —CN;

R₂ is hydrogen; and

R₃ is Cy₁, which is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon; R₁ and R₂ are hydrogen;and R₃ is Cy₁, which is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon:

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferablyhydrogen or —CN;

R₂ is hydrogen; and

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and wherein said Cy₁ is optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, 13 OR₈ or —SR₈, and more preferablyhydrogen or —CN;

R₂ is hydrogen; and

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to6-membered, saturated monocyclic ring, which is carbocyclic orheterocyclic containing from 1 to 3 heteroatoms independently selecteefrom N, S and O, wherein said ring is bonded to the rest of the moleculethrough any available C atom, and wherein one or more C or S ring atomsare optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁in R₃ is piperidinyl or pyrrolidinyl, even more preferablypiperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionallysubstituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, andmore preferablyhydrogen or —CN;

R₂ is hydrogen; and

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry.

In another embodiment, the invention relates to the compounds of formulaII wherein A is nitrogen and B is carbon;

R₁ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, halogen, —CN, —OR₈ or —SR₈,preferably hydrogen, halogen, —CN, —OR₈ or —SR₈, and more preferablyhydrogen or —CN;

R₂ is hydrogen; and

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry,

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen; and

R₅ is hydrogen.

In another embodiment the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon; R₁ and R₂ are hydrogen;and R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₅ is hydrogen; and

R₆ is hydrogen or C₁₋₄alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁ and R₂ are hydrogen; R₅ is hydrogen; and R₆ ishydrogen or C₁₋₄alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₅ is hydrogen; and

R₆ is C₁₋₄alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein R₁ and R₂ are hydrogen; R₅ is hydrogen; and R₆ isC₁₋₄alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ and R₂ are hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and wherein said Cy₁ is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to6-membered, saturated monocyclic ring, which is carbocyclic orheterocyclic containing from 1 to 3 heteroatoms independently selectedfrom N, S and O, wherein said ring is bonded to the rest of the moleculethrough any available C atom, and wherein one or more C or S ring atomsare optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁in R₃ is piperidinyl or pyrrolidinyl, even more preferablypiperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionallysubstituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₅ is hydrogen; and

R₆ is hydrogen or C₁₋₄alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon.

R₁ and R₂ are hydrogen;

R₅ is hydrogen; and

R₆ is hydrogen or C₁₋₄alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₅ is hydrogen; and

R₆ is C₁₋₄alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein A is nitrogen and B is carbon;

R₁ and R₂ are hydrogen;

R₅ is hydrogen; and

R₆ is C₁₋₄alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀; and

R₆ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is CH;

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀; and

R₅ is hydrogen,

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and wherein said Cy₁ is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to6-membered, saturated monocyclic ring, which is carbocyclic orheterocyclic containing from 1 to 3 heteroatoms independently selectedfrom N, S and O, wherein said ring is bonded to the rest of the moleculethrough any available C atom, and wherein one or more C or S ring atomsare optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁in R₃ is piperidinyl or pyrrolidinyl, even more preferablypiperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionallysubstituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaII wherein:

W is CH;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is N;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is N;

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is N;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl; and

R₅ is hydrogen,

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is N;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀; and

R₅ is hydrogen,

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is N;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and wherein said Cy₁ is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

W is N;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to6-membered, saturated monocyclic ring, which is carbocyclic orheterocyclic containing from 1 to 3 heteroatoms independently selectedfrom N, S and O, wherein said ring is bonded to the rest of the moleculethrough any available C atom, and wherein one or more C or S ring atomsare optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁in R₃ is piperidinyl or pyrrolidinyl, even more preferablypiperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionallysubstituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon;

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and wherein said Cy₁ is optionally substituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to6-membered, saturated monocyclic ring, which is carbocyclic orheterocyclic containing from 1 to 3 heteroatoms independently selectedfrom N, S and O, wherein said ring is bonded to the rest of the moleculethrough any available C atom, and wherein one or more C or S ring atomsare optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁in R₃ is piperidinyl or pyrrolidinyl, even more preferablypiperidin-3-yl or pyrrolidin-3-yl, wherein said Cy₁ is optionallysubstituted with one or more R₁₀; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionallysubstituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orR₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferablyhydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl, or Cy₂-C₀₋₄alkyl,preferably hydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ areoptionally substituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orR₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferablyhydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionallysubstituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orR₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferablyhydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁ which is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionallysubstituted with one or more R₁₁;

R₆ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orR₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferablyhydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and wherein said Cy₁ is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionallysubstituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orR₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferablyhydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to6-membered, saturated monocyclic ring, which is carbocyclic orheterocyclic containing from 1 to 3 heteroatoms independently selectedfrom N, S and O, wherein said ring is bonded to the rest of the moleculethrough any available C atom, and wherein one or more C or S ring atomsare optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁in R₃ is piperidinyl or pyrrolidinyl, even more preferablypiperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionallysubstituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionallysubstituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orR₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferablyhydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionallysubstituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orR₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferablyhydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon;

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or C₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionallysubstituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orR₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferablyhydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionallysubstituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orR₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferablyhydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon:

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and wherein said Cy₁ is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂;

wherein Cy₂ are optionally substituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orR₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferablyhydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI or II wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to6-membered, saturated monocyclic ring, which is carbocyclic orheterocyclic containing from 1 to 3 heteroatoms independently selectedfrom N, S and O, wherein said ring is bonded to the rest of the moleculethrough any available C atom, and wherein one or more C or S ring atomsare optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁in R₃ is piperidinyl or pyrrolidinyl, even more preferablypiperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionallysubstituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ are optionallysubstituted with one or more R₁₁;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orR₁₂R₇N—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl and more preferablyhydrogen, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaI wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ is optionallysubstituted with one or more R₁₁; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI wherein:

A is nitrogen and B is carbon;

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ is optionallysubstituted with one or more R₁₁; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ is optionallysubstituted with one or more R₁₁; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and wherein said Cy₁ is optionally substituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ is optionallysubstituted with one or more R₁₁; and

R₅ is hydrogen.

In another embodiment, the invention relates to the compounds of formulaI wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5 to6-membered, saturated monocyclic ring, which is carbocyclic orheterocyclic containing from 1 to 3 heteroatoms independently selectedfrom N, S and O, wherein said ring is bonded to the rest of the moleculethrough any available C atom, and wherein one or more C or S ring atomsare optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁in R₃ is piperidinyl or pyrrolidinyl; wherein said Cy₁ is optionallysubstituted with one or more R₁₀;

R₄ is hydrogen, C₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl or Cy₂-C₀₋₄alkyl, preferablyhydrogen, C₁₋₄alkyl, —NR₇R₁₂ or Cy₂; wherein Cy₂ is optionallysubstituted with one or more R₁₁; and

R₅ is hydrogen.

In another embodiment the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orNR₇R₁₂—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl, more preferablyC₁₋₄alkyl and even more preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ and R₂ are hydrogen;

R₃ is R₉—C₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ areoptionally substituted with one or more R₁₀;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orNR₇R₁₂—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl, more preferablyC₁₋₄alkyl and even more preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, which is optionally substituted with one or more R₁₀;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orNR₇R₁₂—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl, more preferablyC₁₋₄alkyl and even more preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN,more preferably hydrogen; and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered monocyclic ring,which is saturated, partially unsaturated or aromatic, and which iscarbocyclic or heterocyclic containing from 1 to 3 heteroatomsindependently selected from N, S and O, wherein said ring is bonded tothe rest of the molecule through any available C atom, and wherein oneor more C or S ring atoms are optionally oxidized forming CO, SO or SO₂;and wherein said Cy₁ is optionally substituted with one or more R₁₀;

R₅ is hydrogen: and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orNR₇R₁₂—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl, more preferablyC₁₋₄alkyl and even more preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen, halogen, —CN, —OR₈ or —SR₈, preferably hydrogen or —CN;and R₂ is hydrogen;

R₃ is Cy₁, wherein Cy₁ in R₃ is a 3- to 7-membered, preferably 5- to6-membered, saturated monocyclic ring, which is carbocyclic orheterocyclic containing from 1 to 3 heteroatoms independently selectedfrom N, S and O, wherein said ring is bonded to the rest of the moleculethrough any available C atom, and wherein one or more C or S ring atomsare optionally oxidized forming CO, SO or SO₂; and more preferably Cy₁in R₃ is piperidinyl or pyrrolidinyl, even more preferablypiperidin-3-yl or pyrrolidin-3-yl; wherein said Cy₁ is optionallysubstituted with one or more R₁₀;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orNR₇R₁₂—C₁₋₄alkyl, preferably hydrogen or C₁₋₄alkyl, more preferablyC₁₋₄alkyl, and even more preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a) or Cy_(1b);

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferablyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl,R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and evenmore preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen; and

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferablyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl,R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and evenmore preferably methyl or ethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

R₃ is a cycle of formula Cy_(1a) or Cy_(1b);

R₅ is hydrogen;

R₁₀ is —COR₁₃ or —SO₂R(₁₃ and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

W is CH;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

W is N;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII herein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen; and

R₁₀ is —COR₁₃.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₁₀ is —COR_(1a); and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

R₃ is a cycle of formula Cy_(1a) or Cy_(1b);

R₅ is hydrogen;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferablyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl,R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and evenmore preferably methyl or ethyl;

R₁₀ is —COR₁₃ or —SO₂R₁₃;and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferablyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl,R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and evenmore preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a) or Cy_(1b);

R₅ is hydrogen;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferablyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl,R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and evenmore preferably methyl or ethyl; and

R₁₀ is —COR₁₃ or —SO₂R₁₃.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferablyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl,R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and evenmore preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

W is CH;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferablyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl,R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and evenmore preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

W is N;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with (S)-stereochemistry;

R₅ is hydrogen;

R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, preferablyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, R₁₂R₇N—C₁₋₄alkyl,R₁₆CO—C₀₋₄alkyl or R₁₆CO₂—C₀₋₄alkyl, more preferably C₁₋₄alkyl, and evenmore preferably methyl or ethyl.

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkylor cyanoC₁₋₄alkyl, preferably C₁₋₄alkyl or cyanoC₁₋₄alkyl, and morepreferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with the(S)-stereochemistry;

R₅ is hydrogen:

R₆ is C₁₋₄alkyl, preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

W is CH;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with the(S)-stereochemistry;

R₅ is hydrogen;

R₆ is C₁₋₄alkyl, preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

W is N;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a), preferably with the(S)-stereochemistry;

R₅ is hydrogen;

R₆ is C₁₋₄alkyl, preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1a) with the (S)-stereochemistry;

R₅ is hydrogen;

R₆ is C₁₋₄alkyl, preferably methyl or ethyl;

R₁₀ is —COR₁₃; and

R₁₃ is C₁₋₄alkyl or cyanoC₁₋₄alkyl, preferably methyl or cyanomethyl.

In another embodiment, the invention relates to the compounds of formulaII wherein:

A is nitrogen and B is carbon;

R₁ is hydrogen or —CN, preferably hydrogen; and R₂ is hydrogen;

R₃ is a cycle of formula Cy_(1b);

R₅ is hydrogen;

R₆ is C₁₋₄alkyl, preferably methyl or ethyl; and

R₁₀is —SO₂R₁₃.

Furthermore, the present invention covers all possible combinations ofthe particular and preferred embodiments described above.

In another embodiment, the invention relates to a compound of formula Ior II selected from the list of compounds described in examples 1 to 37.

In another embodiment, the invention relates to a compound of formula Ior II that provides more than 50% inhibition of JAK3 activity at 10 μM,more preferably at 1 μM and still more preferably at 0.1 μM, in a JAK3assay such as the one described in example 38.

In an additional embodiment, the invention relates to a compoundaccording to formula I or II that provides more than 50% inhibition ofJAK2 activity at 10 μM, more preferably at 1 μM and still morepreferably at 0.1 μM, In a JAK2 assay such as the one described inexample 39.

The compounds of the present invention contain one or more basicnitrogens and may, therefore, form salts with organic or inorganicacids. Examples of these salts include: salts with inorganic acids suchas hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,perchloric acid, sulfuric acid or phosphoric acid; and salts withorganic acids such as methanesulfonic acid, trifluoromethanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid,citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid,succinic acid and propionic acid, among others. Some of the compounds ofthe present invention may contain one or more acidic protons and,therefore, they may also form salts with bases. Examples of these saltsinclude: salts with inorganic cations such as sodium, potassium,calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed withpharmaceutically acceptable amines such as ammonia, alkylamines,hydroxylalkylamines, lysine, arginine, N-methylglucamine, procaine andthe like.

There is no limitation on the type of salt that can be used, providedthat these are pharmaceutical acceptable when they are used fortherapeutic purposes, The term pharmaceutically acceptable salt refersto those salts which are, according to medical judgment, suitable foruse in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like.Pharmaceutically acceptable salts are well known in the art.

The salts of a compound of formula I or II can be obtained during thefinal isolation and purification of the compounds of the invention orcan be prepared by treating a compound of formula I or II with asufficient amount of the desired acid or base to give the salt in theconventional manner. The salts of the compounds of formula I or II canbe converted into other salts of the compounds of formula I or II by ionexchange using ionic exchange resins.

The compounds of formula I or II and their salts may differ in somephysical properties but they are equivalent for the purposes of thepresent invention. All salts of the compounds of formula I or II areincluded within the scope of the invention.

The compounds of the present invention may form complexes with solventsin which they are reacted or from which they are precipitated orcrystallized. These complexes are known as solvates. As used herein, theterm solvate refers to a complex of variable stoichiometry formed by asolute (a compound of formula I or II or a salt thereof) and a solvent.Examples of solvents include pharmaceutically acceptable solvents suchas water, ethanol and the like. A complex with water is known as ahydrate. Solvates of compounds of the invention (or salts thereof),including hydrates, are included within the scope of the invention.

The compounds of formula I or II may exist in different physical forms,i.e. amorphous and crystalline forms. Moreover, the compounds of theinvention may have the ability to crystallize in more than one form, acharacteristic which is known as polymorphism. Polymorphs can bedistinguished by various physical properties well known in the art suchas X-ray diffraction pattern, melting point or solubility. All physicalforms of the compounds of formula I or II, including all polymorphicforms (“polymorphs”) thereof, are included within the scope of theinvention.

Some of the compounds of the present invention may exist as severaldiastereoisomers and/or several optical isomers. Diastereoisomers can beseparated by conventional techniques such as chromatography orfractional crystallization. Optical isomers can be resolved byconventional techniques of optical resolution to give optically pureisomers. This resolution can be carried out on any chiral syntheticintermediate or on products of formula I or II. Optically pure isomerscan also be individually obtained using enantiospecific synthesis. Thepresent invention covers all individual isomers as well as mixturesthereof (for example racemic mixtures or mixtures of diastereomers),whether obtained by synthesis or by physically mixing them.

The present invention further covers all unlabeled and isotopicallylabeled forms of the compounds of formula I or II.

The present invention further covers all tautomeric forms of thecompounds of formula I or II.

The compounds of formula I or II can be obtained by following theprocesses described below. As it will be obvious to one skilled in theart, the exact method used to prepare a given compound may varydepending on its chemical structure. Moreover, in some of the processesdescribed below it may be necessary or advisable to protect the reactiveor labile groups with conventional protecting groups. Both the nature ofthese protecting groups and the procedures for their introduction andremoval are well known in the art (see for example Greene T. W. and WutsP. G. M, “Protecting Groups in Organic Synthesis”, John Wiley & Sons,3^(rd) edition, 1999). As an example, as protecting group of an aminofunction the tert-butoxycarbonyl (BOC) group can be used. Whenever aprotecting group is present a later deprotection step will be required,which can be performed under standard conditions in organic synthesis,such as those described in the above-mentioned reference.

In general, compounds of formula I or II can be obtained from a compoundof formula VI, as shown in the following scheme:

wherein A, B, W, R₁, R₂, R₃, R₄ and R₅ have the meaning previouslydescribed in relation with a compound of formula I or II; R₆ in acompound of formula V or IIb has the meaning previously described inrelation with a compound of formula I or II, except hydrogen; and X is aleaving group.

The compounds of formula I can be obtained by reacting a compound offormula VI with either the corresponding isothiocyanate III or aldehydeIV.

The reaction with an isothiocyanate III may be performed in the presenceof 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, in a suitable solventsuch as dichloromethane, and heating at a suitable temperature usuallycomprised between 100 and 200° C. The heating may be thermal or byirradiating with microwaves at a wattage that allows reaching thetemperature mentioned above.

The reaction between compounds of formula VI and IV can be carried outin a suitable solvent such as ethanol, butanol, N,N-dimethylformamide ordimethylacetamide, in the presence of an acid such as acetic acid,p-toluenesulfonic acid or sodium bisulfite, and heating, preferably at atemperature comprised between 100 and 200° C. The heating may be thermalor by irradiating with microwaves at a wattage that allows reaching thetemperature mentioned above. When required, the reaction can becompleted by subsequent addition of water.

The compounds of formula II (i.e. compounds of formula IIa and IIb) canbe obtained from a compound of formula VI.

The compounds of formula IIa (i.e. a compound of formula II wherein R₆is hydrogen) can be obtained by reaction of a compound of formula VIwith a synthetic equivalent for the CO synthon. Any such syntheticequivalent disclosed in the literature can in principle be used, forexample 1,1′-carbonyldiimidazole (CDI), phosgene, diphosgene ortriphosgene. The reaction is conducted in the presence of a base such asN,N-diisopropylethylamine; and in a suitable solvent such astetrahydrofuran (THF), and preferably at room temperature. The reactioncan be completed by subsequent addition of water.

The compounds of formula IIb (i.e. a compound of formula II wherein R₆is different from hydrogen) can be obtained by alkylation of a compoundof formula IIa with an alkylating agent R₆-X (V), wherein X represents aleaving group and R₆ is different from H; suitable examples of X includeamong others halogen such as Cl, Br or I, mesylate, tosylate ortriflate. This reaction may be carried out in the presence of a basesuch as Cs₂CO₃, K₂CO₃, NaOH, tert-BuOK or NaH, in a suitable solvent,such as acetone, toluene, 1,2-dimethoxyethane, and preferablydimethylformamide, at a suitable temperature, comprised between 0° C.and reflux.

The compounds of formula VI can be obtained by reduction of a compoundof formula VII as shown in the following scheme:

wherein A, B, W, R₁, R₂, R₃ and R₅ have the meaning previously describedin relation with a compound of formula I or II.

The reaction may be carried out with hydrogen gas, using a platinumcatalyst, such as Pt/C in the presence of thiophene indiisopropylethylamine; in a suitable solvent such as EtOH and preferablyat room temperature.

The compounds of formula VII can be obtained by reacting a compound offormula VIII with either a compound of formula IX or X, as shown in thefollowing scheme:

wherein A, B, W, R₁, R₂, R₃ and R₅ has the meaning previously describedin relation with a compound of formula I or II; and BY₂ is a boronicacid or ester.

The reaction between compounds of formula VIII and IX may be carried outusing the conditions described in the literature for Suzuki's couplingreactions. For example, the reaction may be carried out in the presenceof a Pd catalyst such as Pd(PPh₃)₄; in the presence of a base such asNa₂CO₃; in a mixture of solvents such as a dimethoxyethane and water;and heating.

The direct coupling between compounds of formula VIII and X can beperformed using a palladium catalyst such as for exampletetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄) and preferablypaladium(II) acetate Pd(OAc)₂ in the presence of triphenylphosphine, anda base, such as for example triethylamine and preferably potassiumacetate. The reaction is usually carried out under anhydrous andanaerobic conditions. The reaction may be carried out in a solvent suchas dioxane, N,N-dimethylformamide, toluene and preferably indimethylacetamide and heating at a temperature usually comprised between60° C.-100° C.

Compounds of formula IX and formula X can be easily obtained fromcommercial compounds by known methods.

Additionally, the compounds of formula VII wherein A is nitrogen and Bis carbon (i.e. VIIa) can be obtained by reacting a compound of formulaXI with a compound of formula XII, as shown in the following scheme:

wherein W, R₁, R₂, R₃ and R₅ have the meaning previously described inrelation with a compound of formula I or II; and An is iodine,2,4-dinitrophenolate, p-toluensulphonate or2,4,6-trimethylbencenosulphonate.

The reaction may be carried out in the presence of tetra-n-butylammoniumfluoride (TBAF) in THF and of a base such as1,5-diazabicyclo[4.3.0]non-5ene (DBN) or 1,4-diazabicyclo[2.2.2]octane(DABCO), preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in asolvent such as N,N-dimethylformamide, dimethylsulfoxide,dichloromethane, toluene or acetonitrile, preferably acetonitrile, andat a temperature comprised between −78° C. and room temperature.

Alternatively the compounds of formula VIIa can be obtained by reactinga compound of formula XII with the deprotected derivative of thecompound of formula XI (XIb) obtained by using standard conditions.

The compounds of formula XII can be obtained by reaction of a compoundof formula XIII with aminosulfonic acid in the presence of a H1 aqueoussolution; and of a base such as K₂CO₃, NaOH or KOH; in a solvent such asdichloromethane, tetrahydrofuran, water, ethanol, methanol, isopropanolor acetonitrile; and heating preferably at reflux, as shown in thefollowing scheme:

wherein R₁ and R₂ have the meaning previously described in relation witha compound of formula I or II; and An has the meaning described above.

The compounds of formula XI can be obtained by reaction of a compound offormula VIII with trimethylsilylacetylene, as shown in the followingscheme:

wherein W, R₃ and R₅ have the meaning previously described in relationwith a compound of formula I or II.

The reaction trimethylsilylacetylene may be carried out underSonogashira conditions, using a palladium catalyst such as for exampletetrakis(triphenylphosphino)palladium(0) (Pd(PPh₃)₄), preferablybis(triphenylphosphino)dichloropalladium(II) (Pd(Ph₃P)₂Cl₂) in thepresence of triphenylphospine, a Cu(I) catalyst as a cocatalyst, such asCuI, and a base, such as diethylamine, N,N-diisopropylethylamine,triethylamine or isopropylethylamine. The reaction is usually carriedout under anhydrous and anaerobic conditions. The reaction may becarried out in a solvent such as dioxane, N,N-dimethylformamide,tetrahydrofuran or toluene, at room temperature or by heating.

The compounds of formula VIII can be obtained by reaction of a compoundof formula XIV with a compound of formula XV, as shown in the followingscheme:

wherein W, R₃ and R₅ have the meaning previously described in relationwith a compound of formula I or II.

The reaction between the compounds of formula XIV and XV may be carriedout in the presence of a base such as diisopropylethylamine,diethylamine or triethylamine, in a suitable solvent such as THF oracetonitrile, and at a temperature comprised between −78° C. and roomtemperature.

The compounds of formula XIV and XV are commercial or may be easilyobtained from commercial compounds using standard procedures.

Furthermore, some compounds of the present invention can also beobtained from other compounds of formula I or II by appropriateconversion reactions of functional groups in one or several steps, usingwell-known reactions in organic chemistry under the standardexperimental conditions. Said transformations can be carried out forexample upon R₃ and include, for example the substitution of a primaryor secondary amine by treatment with an alkylating agent, the reactionof an acid or ester with an amine to obtain the corresponding amide, theconversion of an amine into a sulfonamide and the hydrolysis of an esterto obtain a carboxylic acid. In some of these conversions it may benecessary or advisable to protect the reactive or unstable groups bymeans of conventional protective groups.

As it will be obvious to those skilled in the art, these interconversionreactions can be carried out upon the compounds of formula I or II aswell as upon any suitable synthesis intermediate thereof.

As mentioned above, the compounds of the present invention act byinhibiting JAK/STAT signaling pathways, particularly by inhibiting JAK3activity. Therefore, the compounds of the invention are expected to beuseful to treat or prevent diseases in which JAKs, particularly JAK3,play a role in mammals, including human beings. These diseases include,but are not limited to, transplant rejection; immune, autoimmune andinflammatory diseases; neurodegenerative diseases; and proliferativedisorders (see e.g. O'Shea J. J. et al, Nat. Rev. Drug. Discov. 2004,3(7):555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004,10(15):1767-84; Cetkovic-Cvrlje M. et al, Arch. Immunol. Ther. Exp.(Warsz), 2004, 52(2):68-82).

Acute or chronic transplant rejection reactions that can be treated orprevented with the compounds of the present invention include any kindof cell, tissue or organ xenotransplants or allografts, such as ofheart, lung, liver, kidney, pancreas, uterus, joints, pancreatic islets,bone marrow, limbs, cornea, skin, hepatocytes, pancreatic beta cells,pluripotential cells, neuronal cells and myocardial cells, as well asgraft-versus-host reactions (see e.g. Rousvoal G. et al, Transpl. Int.2006, 19(12):1014-21; Borie D C, et al, Transplantation 2005,79(7):791-801; Paniagua R. et al, Transplantation 2005, 80(9):1283-92;Higuchi T. et al, J. Heart Lung Transplant. 2005, 24(10):1557-64;Säemann MD. et al, Transpl Int. 2004, 17(9):481-89; Silva Jr H T. et al,Drugs 2006, 66(13):1665-1684).

Immune, autoimmune or inflammatory diseases that can be treated orprevented with the compounds of the present invention include amongothers, rheumatic diseases (e.g. rheumatoid arthritis and psoriaticarthritis), autoimmune hematological disorders (e.g. hemolytic anemia,aplastic anemia, idiopathic thrombocytopenia, and neutropenia),autoimmune gastritis and inflammatory bowel diseases (e.g. ulcerativecolitis and Crohn's disease), scleroderma, type I diabetes andcomplications from diabetes, type B hepatitis, type C hepatitis, primarybiliary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupuserythematosus, psoriasis, atopic dermatitis, contact dermatitis, eczema,skin sunburns, suppression of HIV replication, infertility of autoimmuneorigin, autoimmune thyroid disease (Grave's disease), interstitialcystitis, mast cell-mediated allergic reactions such as asthma,angiodema, anaphylaxis, bronchitis, rhinitis and sinusitis, andinflammatory or autoimmune ocular diseases such as dry eye syndrome,glaucoma, Sjögren's syndrome, uveitis and retinopathy of prematurity(see e.g. Sorbera L A, et al, Drugs of the Future 2007, 32(8):674-680;O'Shea J. J, et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64;Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84;Muller-Ladner U. et al, J. Immunol. 2000, 164(7): 3894-3901; Walker J G.et al, Ann. Rheum. Dis. 2006, 65(2):149-56; Millci A J. et al, ArthritisRheum. 2006, 54 (9, Suppl): abstr 789; Kremer J M. et al, ArthritisRheum. 2006, 54, 4116, presentation no. L40; Cetkovic-Cvrlje M. et al,Arch Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82; Malaviya R. et al,J. Pharmacol. Exp. Ther. 2000, 235(3):912-26; Malaviya R. et al, J.Biol. Chem. 1999, 274(38):27028-38; Wilkinson B e al, Ann. Rheum. Dis.2007, 66(Suppl 2): Abst. THU0099; Matsumoto M. et al, J. Immunol. 1999,162(2):1056-63, West K., Curr Opin Inventig Drugs 2009:10(5):491-504,Huang Y. et al., Exp Eye res 2007:85(5):684-95, Killedar S Y et al,Laboratory Investigation 2006:86:1243-1280, Egwuagu C. E., Cytokine2009:47(3):149-156, Byfield G., Investigative Ophtalmology & ViralScience 2009:50:3360).

Neurodegenerative diseases that can be treated or prevented with thecompounds of the present invention include, among others, amyotrophiclateral sclerosis and Alzheimer's disease (see e.g. Trieu V N et al,Biochem. Biophys. Res. Commun. 2000, 267(1):22-5).

Proliferative disorders that can be treated or prevented with thecompounds of the present invention include, among others, leukemias,lymphomas, glioblastoma multiforme, colon carcinoma, as well asthromboembolic and allergic complications associated with these diseases(see e.g. Sudbeck E A. et al, Clin. Cancer Res. 1999, 5(6):1569-82;Narla R K. et al, Clin. Cancer Res. 1998, 4(10):2463-71; Lin Q. et al,Am J. Pathol. 2005, 167(4):969-80; Tibbles H E. et al, J. Biol. Chem.2001, 276(21):17815-22).

It has been found that certain compounds of formula I or II, besidesinhibiting JAK3 activity, also inhibit JAK2 kinase to varying degrees,and therefore can also be useful for the treatment or prevention of anydisease mediated by JAK2 kinase. A group of such JAK2-mediated diseasesare myeloproliferative disorders, including polycythemia vera, essentialthrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia,hypereosinophilic syndrome, chronic neutrophilic leukemia, chronicmyelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronicbasophilic leukemia, chronic eosinophilic leukemia, systemicmastocytosis and myelodisplastic syndrome (see e.g. Geron I. et al,Cancer cell 2008, 13:321-330; Pardanani A. et al, Leukemia 2007, 21(8):1658-68; Mathur A. et al, Biochem Pharmacol 2009, 78(4):382-9;Manshouri T. et al, Cancer Sci. 2008, 99(6):1265-73; Wernig G. et al,Cancer cell 2008, 13(4):311-20. Elizabeth O. et al, Blood, 111(12:-5663-5671).

Compounds of formula I or II wherein R₁ and R₂ are hydrogen have beenfound to be particularly useful as JAK2 inhibitors, and thus can beparticularly useful, in addition to treating or preventing all thediseases mentioned in the preceding paragraphs, also for the treatmentor prevention of myeloproliferative disorders (MPD).

Thus, another aspect of the invention relates to a compound of formula Ior II, or a pharmaceutically acceptable salt thereof for use in thetreatment or prevention of a disease mediated by JAK2. More preferably,the disease mediated by JAK2 is a myeloproliferative disorder. In apreferred embodiment, the compounds of formula I or II are those whereinR₁ and R₂ are hydrogen.

Another aspect of the present invention relates to the use of a compoundof formula I or II or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment or prevention of a diseasemediated by JAK2. More preferably, the disease mediated by JAK2 is amyeloproliferative disorder. In a preferred embodiment, the compounds offormula I or II are those wherein R₁ and R₂ are hydrogen.

Another aspect of the present invention relates to a method of treatingor preventing a disease mediated by JAK2 in a subject in need thereof,especially a human being, which comprises administering to said subjecta compound of formula I or II, or a pharmaceutically acceptable saltthereof. More preferably, the disease mediated by JAK2 is amyeloproliferative disease. In a preferred embodiment, the compounds offormula I or II are those wherein R₁ and R₂ are hydrogen

Another aspect of the invention relates to a compound of formula I orII, or a pharmaceutically acceptable salt thereof for use in thetreatment or prevention of a myeloproliferative disorder. In a preferredembodiment, the myeloproliferative disorder is selected frompolycythemia vera, essential thrombocytosis, idiopathic myelofibrosis,chronic myelogenous leukemia, hypereosinophilic syndrome, chronicneutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosiswith myeloid metaplasia, chronic basophilic leukemia, chroniceosinophilic leukemia, systemic mastocytosis and myelodisplasticsyndrome. In a preferred embodiment, the compounds of formula I or IIare those wherein R₁ and R₂ are hydrogen.

Another aspect of the invention relates to the use of a compound offormula I or II or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment or prevention of amyeloproliferative disorder. In a preferred embodiment, themyeloproliferative disorder is selected from polycythemia vera,essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenousleukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia,chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia,chronic basophilic leukemia, chronic eosinophilic leukemia, systemicmastocytosis and myelodisplastic syndrome. In a preferred embodiment,the compounds of formula I or II are those wherein R₁ and R₂ arehydrogen.

Another aspect of the present invention relates to a method of treatingor preventing a myeloproliferative disorder in a subject in needthereof, especially a human being, which comprises administering to saidsubject a compound of formula I or II or a pharmaceutically acceptablesalt thereof. In a preferred embodiment, the myeloproliferative disorderis selected from polycythemia vera, essential thrombocytosis, idiopathicmyelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome,chronic neutrophilic leukemia, chronic myelomonocytic leukemia,myelofibrosis with myeloid metaplasia, chronic basophilic leukemia,chronic eosinophilic leukemia, systemic mastocytosis and myelodisplasticsyndrome. In a preferred embodiment, the compounds of formula I or IIare those wherein R₁ and R₂ are hydrogen.

Biological assays that can be used to determine the ability of acompound to inhibit JAKs, particularly JAK3 and JAK2, are well known inthe art. For example, a compound to be tested can be incubated in thepresence of the desired JAK, such as JAK3 or JAK2, to determine whetherinhibition of JAK enzymatic activity occurs, as described in the assayof examples 38 and 39 for JAK3 and JAK2, respectively. Other in vitrouseful assays that can be used to measure JAK3-inhibitory activityinclude cellular assays, for example IL-2-induced proliferation of humanT lymphocytes. The immunosuppressive activity of the compounds of theinvention can be tested using standard in vivo animal models for immuneand autoimmune diseases, which are well known in the art. For example,the following assays can be used: delayed-type hypersensitivity (DTH)(see e.g. the method disclosed in Kudlacz E. et al, Am J. Transplant.2004, 4(1):51-7, the contents of which are incorporated herein byreference), rheumatoid arthritis models such as collagen-inducedarthritis (see e.g. the method disclosed in Holmdahl R et al, APMIS,1989, 97(7):575-84, the contents of which are incorporated herein byreference), multiple sclerosis models such as experimental autoimmuneencephalomyelitis (EAE) (see e.g. the method disclosed in González-Reyet al, Am. J. Pathol. 2006, 168(4): 1179-88, the contents of which areincorporated herein by reference) and transplant rejection models (seee.g. the various animal models disclosed in the references listed abovein relation to the treatment of transplant rejection, incorporatedherein by reference). The antiproliferative activity of the compounds ofthe invention can be tested using standard in vivo animal models wellknown in the art, such as xenograft studies (see e.g Mohammad R H. etal, Pancreas. 1998; 16(1):19).

For selecting active compounds for JAK3, testing at 10 μM must result inan activity of more than 50% inhibition of JAK3 activity in the testprovided in example 38. More preferably, when tested in this assaycompounds should exhibit more than 50% inhibition at 1 μM, and stillmore preferably, they should exhibit more than 50% inhibition at 0.1 μM.

For selecting active compounds for JAK2, testing at 10 μM must result inan activity of more than 50% inhibition of JAK2 activity in the testprovided in example 39 More preferably, when tested in this assaycompounds should exhibit more than 50% inhibition at 1 μM, and stillmore preferably, they should exhibit more than 50% inhibition at 0.1 μM.

Assays that can be used to predict the PK profile of a compound are wellknown in the art. For example, a Caco-2 assay can be used to determinein vitro the potential for oral absorption of a compound. To show a goodPK profile the compound must also exhibit a suitable clearance, asdetermined in a standard test using for example human liver microsomesin an assay such as the one described in example 40.

Standard assays can be used to assess potential toxic effects of drugcandidates, all of which are well known in the art. Such tests includee.g. viability assays in different cell lines such as human hepatocytecarcinoma cells (Hep G2), which can be performed following standardprocedures, such as the one described in example 41.

The present invention also relates to a pharmaceutical composition thatcomprises a compound of the present invention (or a pharmaceuticallyacceptable salt or solvate thereof) and one or more pharmaceuticallyacceptable excipients. The excipients must be “acceptable” in the senseof being compatible with the other ingredients of the composition andnot deleterious to the recipients thereof.

The compounds of the present invention can be administered in the formof any pharmaceutical formulation, the nature of which, as it is wellknown, will depend upon the nature of the active compound and its routeof administration. Any route of administration may be used, for exampleoral, parenteral, nasal, ocular, rectal and topical administration.

Solid compositions for oral administration include tablets, granulatesand capsules. In any case the manufacturing method is based on a simplemixture, dry granulation or wet granulation of the active compound withexcipients. These excipients can be, for example, diluents such aslactose, microcrystalline cellulose, mannitol or calciumhydrogenphosphate; binding agents such as for example starch, gelatin orpovidone; disintegrants such as sodium carboxymethyl starch or sodiumcroscarmellose; and lubricating agents such as for example magnesiumstearate, stearic acid or talc. Tablets can be additionally coated withsuitable excipients by using known techniques with the purpose ofdelaying their disintegration and absorption in the gastrointestinaltract and thereby provide a sustained action over a longer period, orsimply to improve their organoleptic properties or their stability. Theactive compound can also be incorporated by coating onto inert pelletsusing natural or synthetic film-coating agents. Soft gelatin capsulesare also possible, in which the active compound is mixed with water oran oily medium, for example coconut oil, mineral oil or olive oil.

Powders and granulates for the preparation of oral suspensions by theaddition of water can be obtained by mixing the active compound withdispersing or wetting agents; suspending agents and preservatives. Otherexcipients can also be added, for example sweetening, flavoring andcolouring agents.

Liquid forms for oral administration include emulsions, solutions,suspensions, syrups and elixirs containing commonly used inert diluents,such as purified water, ethanol, sorbitol, glycerol, polyethyleneglycols (macrogols) and propylene glycol. Said compositions can alsocontain coadjuvants such as wetting, suspending, sweetening, favoringagents, preservatives and buffers.

Injectable preparations, according to the present invention, forparenteral administration, comprise sterile solutions, suspensions oremulsions, in an aqueous or non-aqueous solvent such as propyleneglycol, polyethylene glycol or vegetable oils. These compositions canalso contain coadjuvants, such as wetting, emulsifying, dispersingagents and preservatives. They may be sterilized, by any known method orprepared as sterile solid compositions, which will be dissolved in wateror any other sterile injectable medium immediately before use. It isalso possible to start from sterile materials and keep them under theseconditions throughout all the manufacturing process.

For the rectal administration, the active compound can be preferablyformulated as a suppository on an oily base, such as for examplevegetable oils or solid semisynthetic glycerides, or on a hydrophilicbase such as polyethylene glycols (macrogol).

The compounds of the invention can also be formulated for their topicalapplication for the treatment or prevention of pathologies occurring inzones or organs accessible through this route, such as eyes, skin andthe intestinal tract. Formulations include creams, lotions, gels,powders, solutions and patches wherein the compound is dispersed ordissolved in suitable excipients.

For the nasal administration or for inhalation, the compound can beformulated as an aerosol and it can be conveniently released usingsuitable propellants.

The dosage and frequency of doses will depend upon the nature andseverity of the disease to be treated, the age, the general conditionand body weight of the patient, as well as the particular compoundadministered and the route of administration, among other factors. Arepresentative example of a suitable dosage range is from about 0.01mg/Kg to about 100 mg/Kg per day, which can be administered as a singleor divided doses.

The following examples illustrate the scope of the invention.

EXAMPLES

The following abbreviations have been used in the examples:

-   AcOH: acetic acid-   AcN: acetonitrile-   DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene-   DIPEA: N,N-diisopropylethylamine-   DMAC: N,N-dimethylacetamide-   DMF: N,N-dimethylformamide-   EDC: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide-   EtOAc: ethyl acetate-   EtOH: ethanol-   HATU: 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium    hexafluorophosphate Methanaminium-   HOBt: 1-hydroxybenzotriazole-   HPLC: high performance liquid chromatography-   LC-MS: liquid chromatography-mass spectroscopy-   MeI: iodomethane-   MeOH: methanol-   PTSA: para-toluene sulfonic acid-   TBAF: tetrabutylammonium fluoride-   TBME: tert-butyl methyl ether-   TEA: triethylamine-   TFA: trifluoroacetic acid-   THF: tetrahydrofurane-   TLC: thin layer cromatography-   t_(R): retention time

One of the following methods was used to determine the LC-MS spectrums:

-   Method 1: Column SunFire C18 3.5 μm, (100 mm×2.1), flow rate: 0.3    mL/min, eluent A=CH3CN:MeOH 1:1 B=NH₄Ac 5 mM pH 7, gradient: 0 min    10% A; 17 min 95% A; 10 min 95% A.-   Method 2: Column XBridge, 3.5 μm (50 mm×4.6), temperature: 30° C.,    flow rate: 2 mL/min, eluent A=NH₄HCO₃ 10 mM (pH=9), B=AcN, gradient:    0 min 5% B; 4.8 min 100% B;-   Method 3: Column XBridge, 3.5 μm (50 mm×4.6), temperature: 50° C.,    flow rate: 1.6 mL/min, eluent A=NH₄HCO₃ 10 mM (pH=9), B=AcN,    gradient: 0 min 5% B; 3.5 min 1005% B;-   Method 4 (Palau): Column Waters Acquity UPLC BEH C18 (1.7 μm, 2.1    mm×50 mm), temperature: 40° C., flow: 0.5 mL/min, eluent: ACN    (A)/ammonium bicarbonate 10 mM (B), gradient: 0 min 10% A=3.75 min    90% A-   Method 5:: Column YMC, 3.5 μm (50 mm×4.6), temperature: 50° C., flow    rate: 1.3 mL/min, eluent A=H₂O (0.1% HCOOH), B=AcN (0.1% HCOOH),    gradient: 0 min 5% B; 3.5 min 100% B.

Reference Example 1 1-Amino-4trifluoromethylpyridinium2,4,6-trimethylbenzenesulfonate

To a solution of 4-trifluoromethylpyridine (2.23 g, 15.2 mmol) in CH₂Cl₂(66 mL) at 0° C., O-(mesitylsulfonyl)hydroxylamine (3.27 g, 15.2 mmol)was added. The reaction mixture was stirred at room temperature for 18h. The reaction mixture was filtered to afford the desired product withquantitative yield.

LC-MS (method 4); t_(R)=1.07 min; m/z=199 (MH⁺),

Reference Example 2(S)-3-(4-(1-Acetylpiperidin-3-ylamino)-5-aminopyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Following a similar procedure to that described in example 1 (section ato d), but using (S)-1-acetyl-3-aminopiperidine instead oftetrahydro-2H-pyran-4-amine, the desired compound was obtained.

LC-MS (method 3): t_(R)=1.59 min; m/z=377 (MH⁺).

Following a similar procedure to that described in reference example 2,but using in each case the corresponding starting materials, thefollowing compounds were obtained:

Reference HPLC t_(R) example Name Starting Materials method (min) m/z 2a(S)-tert-butyl 3-(5-amino-2-(5- 1-amino-4- 3 2.32 424methylpyrazolo[1,5-a]pyridin-3- methylpyridiniumyl)pyrimidin-4-ylamino)piperidine-1- 2,4,6- carboxylatetrimethylbenzenesulfonate(1),, (S)-3-amino- (1-tert-butoxycarbonyl)piperidine and 2,4-dichloro-5- nitropyrimidine 2btert-butyl 4-(5-amino-2-(pyrazolo[1,5- 1-aminopyridinium 4 2.00 410a]pyridin-3-yl)pyrimidin-4- iodide,, 4-amino-(1-ylamino)piperidine-1-carboxylate tert- butoxycarbonyl)piperidine and2,4-dichloro-5- nitropyrimidine 2c 2-(pyrazolo[1,5-a]pyridin-3-yl)-N4-1-aminopyridinium 3 1.55 311 (tetrahydro-2H-pyran-4-yl)pyrimidine-iodide, tetrahydro-2H- 4,5-diamine pyran-4-amine and 2,4-dichloro-5-nitropyrimidine 2d (S)-tert-butyl 3-(3-amino-6- 1-aminopyridinium 3 2.43409 (pyrazolo[1,5-a]pyridin-3-yl)pyridin-2- iodide, (S)-3-amino-ylamino)piperidine-1-carboxylate (1-tert- butoxycarbonyl)piperidine and2,6-dichloro-3- nitropyridine 2e 3-(5-amino-4-(8-fluorochroman-4-1-amino-4- 1 9.28 402 ylamino)pyrimidin-2-yl)pyrazolo[1,5-cyanopyridinium 2,4,6- a]pyridine-5-carbonitriletrimethylbenzenesulfonate, 8-fluorochroman- 4-amine and 2,4- dichloro-5-nitropyrimidine 2f (S)-3-(6-(1-acetylpiperidin-3-ylamino)- 1-amino-4- 31.58 377 5-aminopyridin-2-yl)pyrazolo[1,5- cyanopyridinium 2,4,6-a]pyridine-5-carbonitrile trimethylbenzenesulfonate, (S)-1-acetyl-3-aminopiperidin and 2,6-dichloro-3- nitropyridine 2g6-(pyrazolo[1,5-a]pyridin-3-yl)-N2- 1-aminopyridinium 5 1.68 310(tetrahydro-2H-pyran-4-yl)pyridine- iodide, tetrahydro-2H- 2,3-diaminepyran-4-amine and 2,6-dichloro-3- nitropyridine 2h (S)-tert-butyl3-(3-amino-6-(5- 1-amino-4- 3 2.50 434 cyanopyrazolo[1,5-a]pyridin-3-cyanopyridinium 2,4,6- yl)pyridin-2-ylamino)piperidine-1-trimethylbenzenesulfonate, carboxylate (S)-3-amino-(1- tert-butoxycarbonyl)piperidine and 2,6-dichloro-3- nitropyridine 2i3-(5-amino-4-(trans-4- 1-amino-4- 3 1.45 350hydroxycyclohexylamino)pyrimidin-2- cyanopyridinium 2,4,6-yl)pyrazolo[1,5-a]pyridine-5- trimethylbenzenesulfonate, carbonitriletrans-4- aminocyclohexanol and 2,6-dichloro-3- nitropyridine, (1)described by Zhang et al Journal of Heterocyclic Chemistry: 44; 4; 2007;919-922

Example 13-(8-Oxo-9-tetrahydro-2H-pyran-4-yl-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrilea) 2-Chloro-5-nitro-N-tetrahydro-2H-pyran-4-ylpyrimidin-4-amine

To a solution of 2,4-dichloro-5-nitropyrimidine (1.03 g, 5.15 mmol) inTHF (40 mL) at −78° C., DIPEA (2.0 mL, 11.86 mmol) andtetrahydro-2H-pyran-4-amine (0.54 mL, 5.15 mmol) were added. Thereaction mixture was stirred from −78 to −50° C. for 5 h. The crudemixture was quenched with H₂O (50 mL), extracted with EtOAc (3×40 mL)and the combined organic phases were dried over anhydrous Na₂SO₄,filtered and concentrated. The crude product thus obtained waschromatographed over silica gel using EtOAc/hexanes mixtures ofincreasing polarity as eluent, to afford 1.04 g of the desired compound(78% yield).

b)5-Nitro-N-(tetrahydro-2H-pyran-4-yl)-2-[(trimethylsilyl)ethynyl]pyrimidin-4-amine

To a suspension of the compound obtained in the previous section (1.01g. 3.90 mmol), Pd(PPh₃)₂Cl₂ (137 mg, 0.19 mmol) and CuI (37 mg. 0.19mmol) in toluene (40 mL), TEA (1.6 mL, 11.7 mmol) andtrimethylsilylacetylene (0.7 mL, 5.07 mmol) were added. The reactionmixture was stirred at room temperature for 18 h, quenched withsaturated NH₃Cl aqueous solution (70 mL) and extracted with EtOAc (3×40mL). The combined organic phases were dried over anhydrous Na₂SO₄,filtered and concentrated. The crude residue was cromatographed on asilica gel flash system (SP1 Biotage) using EtOAc/hexanes mixtures ofincreasing polarity as eluent to afford 0.96 g of the desired product(77% yield).

c)3-[5-Nitro-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile

To a suspension of the compound obtained in the previous section (500mg, 1.56 mmol) and 1-amino-4-cyanopyridinium2,4,6-trimethylbenzenesulfonate (498 mg, 1.56 mmol) in AcN (30 mL), at0° C., 1 M TBAF solution in THF (1.56 mL, 1.56 mmol) and a solution ofDBU (0.47 mL, 3.12 mmol) in AcN (10 mL) were added. The reaction mixturewas stirred at 0° C. for 5 min and 3 h at room temperature. The reactionmixture was evaporated to dryness. The crude product thus obtained waschromatographed over silica gel using EtOAc/hexanes mixtures ofincreasing polarity as eluent, to afford 227 mg of the desired compound(48% yield).

d)3-[5-Amino-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile

A mixture of the compound obtained in the previous section (119 mg, 0.32mmol) in EtOH (12 mL) was hydrogenated with Pt/C 5% (148 mg, 0.02 mmol)as a catalyst in the presence of thiophene in DIPEA (4% v/v, 9 drops).The reaction mixture was stirred under H₂ (g) atmosphere at roomtemperature for 1.5 h. The reaction mixture was filtered through a plugof Celite® and the solvent was concentrated off to afford 78 mg of thedesired product (71% yield).

e)3-(8-Oxo-9-tetrahydro-2H-pyran-4-yl-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of the compound obtained in the previous section (78 mg,0.23 mmol) in THF (7 mL), 1,1′-carbonyldiimidazole (188 mg, 1.16 mmol)was added. The reaction mixture was stirred at room temperature for 4 h,quenched with saturated NaCl aqueous solution (15 mL) and extracted withEtOAc (3×15 mL). The combined organic phases were dried over anhydrousNa₂SO₄, filtered and concentrated. The crude product thus obtained waschromatographed over silica gel using MeOH/CH₂Cl₂ mixtures of increasingpolarity as eluent, to afford 5.1 mg of the desired compound (61%yield).

LC-MS (method 1): t_(R)=14.25 min; m/z=362 (MH⁺).

Following a similar procedure to that described in example 1, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) Example Name Starting Material method (min) m/z 1a methyl(2R)-2-[2-(5- D-alanine methyl ester 1 14.48 364cyanopyrazolo[1,5-a]pyridin-3-yl)-8- hydrochlorideoxo-7,8-dihydro-9H-purin-9- yl]propanoate 1b (S)-tert-butyl 3-(2-(5-(S)-tert-butyl 3- 2 2.23 461 cyanopyrazolo[1,5-a]pyridin-3-yl)-8-aminopiperidine-1- oxo-7H-purin-9(8H)-yl)piperidine-1- carboxylatecarboxylate 1c (R)-tert-butyl 3-(2-(5- (R)-tert-butyl 3- 2 2.23 461cyanopyrazolo[1,5-a]pyridin-3-yl)-8- aminopiperidine-1-oxo-7H-purin-9(8H)-yl)piperidine-1- carboxylate carboxylate 1d(S)-3-(9-(1-methoxypropan-2-yl)-8- (S)-1-methoxypropan- 2 1.82 350oxo-8,9-dihydro-7H-purin-2- 2-amine yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 1e 3-(9-(4,4-difluorocyclohexyl)-8-oxo- 4,4- 2 2.03 3968,9-dihydro-7H-purin-2- difluorocyclohexanamineyl)pyrazolo[1,5-a]pyridine-5- carbonitrile 1f3-(9-(1,1-dioxotetrahydrothien-3-yl)-8- 3-amino-1,1- 2 1.43 396oxo-8,9-dihydro-7H-purin-2- dioxotetrahydrothiopheneyl)pyrazolo[1,5-a]pyridine-5- carbonitrile 1g3-(9-(2-fluorobenzyl)-8-oxo-8,9- 2-fluorobenzylamine 1 16.58 386dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 1h3-(9-(4-methoxybut-1-yl)-8-oxo-8,9- 4-methoxybutan-1- 1 15.15 396dihydro-7H-purin-2-yl)pyrazolo[1,5- amine a]pyridine-5-carbonitrile 1imethyl (2S)-2-[2-(5- L-alanine methyl ester 3 1.83 436cyanopyrazolo[1,5-a]pyridin-3-yl)-8- hydrochlorideoxo-7,8-dihydro-9H-purin-9- yl]propanoate 1j9-(1-acetylpiperidin-4-yl)-2-(5- 1-acetyl-4- 4 1.68 446(trifluoromethyl)pyrazolo[1,5-a]pyridin- aminopiperidine3-yl)-7H-purin-8(9H)-one(1) hydrochloride 1k (S)-tert-butyl 3-(2-(5-(S)-tert-butyl 3- 5 2.72 447 cyanopyrazolo[1,5-a]pyridin-3-yl)-8-aminopyrrolidine-1- oxo-7H-purin-9(8H)-yl)pyrrolidine-1- carboxylatecarboxylate 1l (R)-tert-butyl 3-(2-(5- (R)-tert-butyl 3- 3 2.25 447cyanopyrazolo[1,5-a]pyridin-3-yl)-8- aminopyrrolidine-1-oxo-7H-purin-9(8H)-yl)pyrrolidine-1- carboxylate carboxylate 1m(S)-tert-butyl 3-(2-(5- (S)-tert-butyl 3- 3 2.47 450methylpyrazolo[1,5-a]pyridin-3-yl)-8- aminopiperidine-1-oxo-7H-purin-9(8H)-yl)piperidine-1- carboxylate carboxylate (2) 1n ethyl2-(2-(5-cyanopyrazolo[1,5- ethyl 2-aminoacetate 3 1.82 364a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)- yl)acetate 1o3-(9-(trans-4-hydroxycyclohexyl)-8- trans-4- 3 1.55 376oxo-8,9-dihydro-7H-purin-2- aminocyclohexanolyl)pyrazolo[1,5-a]pyridine-5- carbonitrile 1p3-(9-(8-fluorochroman-4-yl)-8-oxo-8,9- 8-fluorochroman-4- 1 15.43 428dihydro-7H-purin-2-yl)pyrazolo[1,5- amine a]pyridine-5-carbonitrile 1qtert-butyl 4-(2-(5-cyanopyrazolo[1,5- tert-butyl 4- 3 2.33 461a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)- aminopiperidine-1-yl)piperidine-1-carboxylate carboxylate 1r tert-butyl3-(2-(5-cyanopyrazolo[1,5- tert-butyl 3- 3 2.20 433a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)- aminoazetidine-1-yl)azetidine-1-carboxylate carboxylate 1s9-(1-acetylpiperidin-4-yl)-2-(5- 1-acetyl-4- 4 1.38 392methylpyrazolo[1,5-a]pyridin-3-yl)-7H- aminopiperidine purin-8(9H)-one(2) hydrochloride (1) step c) was performed using reference example 1instead of 1-amino-4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate (2)step c) was performed using 1-amino-4-methylpyridinium2,4,6-trimethylbenzenesulfonate (described by Zhang et al Journal ofHeterocyclic Chemistry; 44; 4; 2007; 919-922) instead of1-amino-4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate

Example 23-(2-Oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carbonitrilea) 6-Chloro-3-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine

To a suspension of 2,6-dichloro-3-nitropyridine (6 g, 31.1 mmol) in AcN(200 mL) at 0° C., TEA (9 mL, 62.2 mmol) and tetrahydro-2H-pyran-4-amine(3.15 g. 31.1 mmol) were added. The reaction mixture was stirred at 0°C. for 1.5 h. The reaction crude was tempered and stirred at roomtemperature for 18 h. The reaction mixture was evaporated under reducedpressure, dissolved in EtOAc, and washed thrice with saturated NaHCO₃aqueous solution. The combined organic phases were dried over MgSO₄ andconcentrated to dryness. The crude residue was cromategraphed on asilica gel flash system (ISCO Combiflash) using hexanes/TBME mixtures ofincreasing polarity as eluent to afford 5.23 g of the desired product(65% yield).

b)3-Nitro-N-(tetrahydro-2H-pyran-4-yl)-6-((trimethylsilyl)ethynyl)pyridin-2-amine

Following a similar procedure to that described in example 1, section b,but using the compound obtained in previous section as startingmaterial, the desired compound was obtained (87% yield).

c)3-(5-Nitro-6-(tetrahydro-2H-pyran-4-ylamino)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Following a similar procedure to that described in example 1, section c,but using the compound obtained in previous section as startingmaterial, the desired compound was obtained (16% yield).

d)3-(5-Amino-6-(tetrahydro-2H-pyran-4-ylamino)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Following a similar procedure to that described in example 1, section d,but using the compound obtained in previous section as startingmaterial, the desired compound was obtained (19% yield).

e) Title Compound

Following s similar procedure to that described in example 1, section e,but using the compound obtained in previous section as startingmaterial, the desired compound was obtained (23% yield).

LC-MS (method 3): t_(R)=1.83 min; m/z=361 (MH⁺)

Following a similar procedure to that described in example 2, but usingin each case the corresponding starting materials, the followingcompounds ware obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 2a(S)-tert-butyl 3-(2-oxo-5- (S)-3-amino-(1-tert- 3 2.47 435(pyrazolo[1,5-a]pyridin-3-yl)-1H- butoxycarbonyl)piperidineimidazo[4,5-b]pyridin-3(2H)- and 1- yl)piperidine-1-carboxylateaminopyridinium iodide 2b (R)-tert-butyl 3-(2-oxo-5- (R)-tert-butyl 3- 32.27 421 (pyrazolo[1,5-a]pyridin-3-yl)-1H- aminopyrrolidine-1-imidazo[4,5-b]pyridin-3(2H)- carboxylate and 1-yl)pyrrolidine-1-carboxylate aminopyridinium iodide 2c (S)-tert-butyl3-(2-oxo-5- (S)-tert-butyl 3- 3 2.27 421(pyrazolo[1,5-a]pyridin-3-yl)-1H- aminopyrrolidine-1-imidazo[4,5-b]pyridin-3(2H)- carboxylate and 1-yl)pyrrolidine-1-carboxylate aminopyridinium iodide 2d (S)-tert-butyl3-(5-(5- (S)-3-amino-(1-tert- 3 2.50 434cyanopyrazolo[1,5-a]pyridin-3-yl)-2- butoxycarbonyl)piperidineoxo-1H-imidazo[4,5-b]pyridin- and 3(2H)-yl)piperidine-1-carboxylate1-amino-4- cyanopyridinium 2,4,6- trimethylbenzenesulfonate 2e5-(pyrazolo[1,5-a]pyridin-3-yl)-3- tetrahydro-2H-pyran-4- 3 1.80 336(tetrahydro-2H-pyran-4-yl)-1H- amine and 1-imidazo[4,5-b]pyridin-2(3H)-one aminopyridinium iodide 2f (R)-tert-butyl3-(2-oxo-5- (R)-3-amino-(1-tert- 4 2.15 435(pyrazolo[1,5-a]pyridin-3-yl)-1H- butoxycarbonyl)piperidineimidazo[4,5-b]pyridin-3(2H)- and 1- yl)piperidine-1-carboxylateaminopyridinium iodide

Example 32-(Pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one

Following a similar procedure to that described in example 1, but using1-aminopyridinium iodide instead of 1-amino-4-cyanopyridinium2,4,6-trimethylbenzenesulfonate, the desired compound was obtained (84%yield).

LC-MS (method 3): t_(R)=1.62 min; m/z=337 (MH⁺).

Following a similar procedure to that described in example 3, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 3a2-(pyrazolo[1,5-a]pyridin-3-yl)-9- (tetrahydro-2H-pyran- 2 1.63 351((tetrahydro-2H-pyran-4-yl)methyl)- 4-yl)methanamine 7H-purin-8(9H)-one3b (S)-tert-butyl 3-(8-oxo-2- (S)-tert-butyl-3- 2 2.33 436(pyrazolo[1,5-a]pyridin3-yl)-7H- aminopiperidine-1-purin-9(8H)-yl)piperidine-1- carboxylate carboxylate 3c9-(2-methoxyethyl)-2-(pyrazolo[1,5- 2-methoxyethylamine 2 1.55 311a]pyridin-3-yl)-7H-purin-8(9H)-one 3d 9-(8-fluorochroman-4-yl)-2-8-fluorochroman-4- 1 16.07 403 (pyrazolo[1,5-a]pyridin-3-yl)-7H- aminepurin-8(9H)-one 3e methyl (2S)-2-(8-oxo-2- L-alanine methyl ester 3 1.73339 (pyrazolo[1,5-a]pyridin-3-yl)-7,8- hydrochloridedihydro-9H-purin-9-yl)propanoate 3f (S)-tert-butyl 3-(8-oxo-2-(S)-tert-butyl 3- 3 2.13 422 (pyrazolo[1,5-a]pyridin-3-yl)-7H-aminopyrrolidine-1- purin-9(8H)-yl)pyrrolidine-1- carboxylatecarboxylate 3g tert-butyl 4-(8-oxo-2-(pyrazolo[1,5- tert-butyl 4- 3 2.35461 a]pyridin-3-yl)-7H-purin-9(8H)- aminopiperidine-1-yl)piperidine-1-carboxylate carboxylate 3h 9-(1-methylpiperidin-4-yl)-2-1-methylpiperidin-4- 4 1.38 350 (pyrazolo[1,5-a]pyridin-3-yl)-7H- aminepurin-8(9H)-one 3i 5-(pyrazolo[1,5-a]pyridin-3-yl)-3- 2,2,6,6- 4 1.48391 (2,2,6,6-tetramethylpiperidin-4-yl)- tetramethylpiperidin-4-1H-imidazo[4,5-b]pyridin-2(3H)-one amine

Example 43-(7-Methyl-8oxo-9-tetrahydro-2H-pyran-4-yl-8,9-dihydro-7H-purin-2yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of example 1 (48 mg, 0.13 mmol) in DMF (6 mL), 55-65% NaHdispersion in mineral oil (7.3 mg, 0.18 mmol) was added and theresulting solution was stirred at room temperature for 10 min. Then MeI(0.015 mL, 0.25 mmol) was added and the reaction mixture was stirred for15 h at room temperature. The reaction mixture was quenched withsaturated NaCl aqueous solution (10 mL) and extracted with EtOAc (3×10mL) and CH₂Cl₂ (2×10 mL). The combined organic phases were dried overanhydrous Na₂SO₄, filtered and concentrated. The crude product thusobtained was chromatographed over silica gel using MeOH/CH₂Cl₂ mixturesof increasing polarity as eluent, to afford 50 mg of the desiredcompound (quantitative yield).

LC-MS (method 1): t_(R)=15.48 min; m/z=376 (MH⁺).

Following a similar procedure to that described in example 4, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) Example Name Starting Material method (min) m/z 4a(S)-tert-butyl 3-(2-(5- Example 1b 2 3.22 475cyanopyrazolo[1,5-a]pyridin-3-yl)- 7-methyl-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate 4b (R)-tert-butyl 3-(2-(5- Example 1c 2 3.22475 cyanopyrazolo[1,5-a]pyridin-3-yl)- 7-methyl-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate 4c 9-(8-fluorochroman-4-yl)-7- Example 3d 116.83 417 methyl-2-(pyrazolo[1,5-a]pyridin- 3-yl)-7H-purin-8(9H)-one

Example 5 (S)-tert-Butyl3-(7-methyl-8-oxo-2-(pyrazolo[1,5-a]pyridine-3-yl)-7H-purin-9(8H)-yl)piperidine-1-carboxylate

To a solution of example 3b (70 mg, 0.160 mmol) in DMF (3.5 mL), at 0°C. ¹BuOK (27 mg, 0.24 mmol) and MeI (0.019 mL, 0.32 mmol) were added.The reaction mixture was stirred at room temperature for 20 min andevaporated to dryness. The crude residue was chromatographed on a silicagel flash system (ISCO Rf) using CH₂Cl₂/MeOH mixtures of increasingpolarity as eluent to afford 64 mg of the desired product (89% yield).

LC-MS (method 3): t_(R)=2.58 min; m/z=450 (MH⁺).

Following a similar procedure to that described in example 5, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 5a7-methyl-2-(pyrazolo[1,5-a]pyridin- example 3 2 1.83 3513-yl)-9-(tetrahydro-2H-pyran-4-yl)- 7H-purin-8(9H)-one 5b3-(1-methyl-2-oxo-3-(tetrahydro-2H- example 2 2 2.62 375pyran-4-yl)-2,3-dihydro-1H- imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 5c9-(2-methoxyethyl)-7-methyl-2- Example 3c 2 1.77 325(pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one 5d7-methyl-2-(pyrazolo[1,5-a]pyridin- Example 3a 2 1.87 3653-yl)-9-[(tetrahydro-2H-pyran-4- yl)methyl]-7H-purin-8(9H)-one 5e3-(9-(4,4-difluorocyclohexyl)-7- Example 1e 2 2.32 410methyl-8-oxo-8,9-dihydro-7H-purin- 2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 5f 3-(9-(1,1-dioxotetrahydrothien-3-yl)- Example 1f 2 1.75410 8,9-dihydro-7-methyl-8-oxopurin-2- yl)pyrazolo[1,5-a]pyridine-5-carbonitrile. 5g (S)-tert-butyl 3-(5-(5- Example 2d 2 2.54 474cyanopyrazolo[1,5-a]pyridin-3-yl)-1- methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1- carboxylate 5h3-(9-(2-fluorobenzyl)-7-methyl-8- Example 1g 1 17.66 400oxo-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile5i 9-(1-acetylpiperidin-4-yl)-7-methyl- Example 1j 4 1.85 4602-(5-(trifluoromethyl)pyrazolo[1,5- a]pyridin-3-yl)-7H-purin-8(9H)-one5j (S)-tert-butyl 3-(1-methyl-2-oxo-5- Example 2a 3 2.73 449(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-carboxylate 5k (S)-tert-butyl 3-(2-(5- Example 1k 3 2.52461 cyanopyrazolo[1,5-a]pyridin-3-yl)-7- methyl-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate 5l (R)-tert-butyl 3-(2-(5- Example 1l 32.50 461 cyanopyrazolo[1,5-a]pyridin-3-yl)-7-methyl-8-oxo-7H-purin-9(8H)- yl)pyrrolidine-1-carboxylate 5m(S)-tert-butyl 3-(7-methyl-8-oxo-2- Example 3f 3 2.40 436(pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-9(8H)-yl)pyrrolidine-1-carboxylate 5n (R)-tert-butyl 3-(1-methyl-2-oxo-5- Example 2b 3 2.50 435(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate 5o (S)-tert-butyl 3-(1-methyl-2-oxo-5-Example 2c 5 2.98 436 (pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)- yl)pyrrolidine-1-carboxylate 5p(S)-tert-Butyl 3-(1-ethyl-2-oxo-5- Example 2a 4 2.57 463(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-carboxylate(1) 5q tert-butyl 4-(7-methyl-8-oxo-2-Example 3g 3 2.68 475 (pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1- carboxylate 5r (S)-tert-butyl3-(7-methyl-8-oxo-2- Example 3b 3 2.62 450(pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-9(8H)-yl)piperidine-1-carboxylate 5s 1-methyl-5-(pyrazolo[1,5-a]pyridin- Example 2e 3 2.02 3503-yl)-3-(tetrahydro-2H-pyran-4-yl)- 1H-imidazo[4,5-b]pyridin-2(3H)-one5t (R)-tert-butyl 3-(1-methyl-2-oxo-5- Example 2f 3 2.73 449(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-carboxylate 5u tert-butyl 4-(2-(5- Example 1q 3 2.68 475cyanopyrazolo[1,5-a]pyridin-3-yl)-7- methyl-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate 5v tert-butyl 3-(2-(5- Example 1r 3 2.47 447cyanopyrazolo[1,5-a]pyridin-3-yl)-7- methyl-8-oxo-7H-purin-9(8H)-yl)azetidine-1-carboxylate (1)ethyl iodide instead of methyl iodide asstarting material.

Example 6

(S)-3-(8-Oxo-9-(piperidin-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrilehydrochloride

To a solution of example 1b (45 mg, 0.10 mmol) in dioxane (3 mL), 4 MHCl solution in dioxane (2 mL, 8.0 mmol) was added. The reaction mixturewas stirred at room temperature for 1 h. The reaction mixture wasevaporated to dryness to give 48 mg of the desired compound (100%yield).

LC-MS (method 2): t_(R)=1.73 min; m/z=361 (MH⁺).

Following a similar procedure to that described in example 6, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Compound name Starting material method (min)(MH⁺) 6a (R)-3-(8-oxo-9-(piperidin-3-yl)-8,9- Example 1c 2 1.73 361dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrilehydrochloride 6b (R)-3-(7-methyl-8-oxo-9-(piperidin- Example 4b 2 2.05375 3-yl)-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5-carbonitrile hydrochloride 6c (S)-3-(7-methyl-8-oxo-9-(piperidin-3-Example 4a 2 2.05 375 yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 6d9-(piperidin-4-yl)-2-(pyrazolo[1,5- Example 3g 2 1.28 336a]pyridin-3-yl)-7H-purin-8(9H)-one 6e(S)-3-(2-oxo-3-(piperidin-3-yl)-2,3- Example 2d 2 1.54 360dihydro-1H-imidazo[4,5-b]pyridin-5- yl)pyrazolo[1,5-a]pyridine-5-carbonitrile hydrochloride 6f (S)-3-(1-methyl-2-oxo-3-(piperidin-3-Example 5g 2 1.68 374 yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile hydrochloride 6g(S)-1-methyl-3-(piperidin-3-yl)-5- Example 5j 1 12.46 349(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-onehydrochloride 6h (S)-3-(7-methyl-8-oxo-9-(pyrrolidin- Example 5k 3 1.62361 3-yl)-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5-carbonitrile hydrochloride 6i (R)-3-(7-methyl-8-oxo-9-(pyrrolidin-Example 5l 3 1.62 361 3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 6j(S)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Example 3f 3 1.23 322(pyrrolidin-3-yl)-7H-purin-8(9H)-one hydrochloride 6k(S)-7-methyl-2-(pyrazolo[1,5- Example 5m 3 1.48 336a]pyridin-3-yl)-9-(pyrrolidin-3-yl)-7H- purin-8(9H)-one hydrochloride 6l(S)-3-(8-oxo-9-(pyrrolidin-3-yl)-8,9- Example 1k 3 1.35 347dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrilehydrochloride (1) 6m (R)-1-methyl-5-(pyrazolo[1,5- Example 5n 3 1.57 335a]pyridin-3-yl)-3-(pyrrolidin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-onehydrochloride 6n (R)-5-(pyrazolo[1,5-a]pyridin-3-yl)-3- Example 2b 31.40 321 (pyrrolidin-3-yl)-1H-imidazo[4,5- b]pyridin-2(3H)-onehydrochloride (1) 6o (R)-3-(8-oxo-9-(pyrrolidin-3-yl)-8,9- Example 1l 31.33 347 dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrilehydrochloride (1) 6p (S)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Example 2c 31.40 321 (pyrrolidin-3-yl)-7H-purin-8(9H)-one hydrochloride 6q(S)-1-methyl-5-(pyrazolo[1,5- Example 5o 3 1.57 335a]pyridin-3-yl)-3-(pyrrolidin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-onehydrochloride 6r (S)-2-(5-methylpyrazolo[1,5- Example 1m 3 1.57 350a]pyridin-3-yl)-9-(piperidin-3-yl)-7H- purin-8(9H)-one hydrochloride 6s(S)-1-ethyl-3-(piperidin-3-yl)-5- Example 5p 4 1.56 363(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-onehydrochloride 6t 7-methyl-9-(piperidin-4-yl)-2- Example 5q 4 1.23 350(pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one hydrochloride 6u(S)-7-methyl-9-(piperidin-3-yl)-2- Example 5r 3 1.67 350(pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one hydrochloride 6v(S)-9-(piperidin-3-yl)-2- Example 3b 3 1.43 336(pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one hydrochloride 6w(R)-1-methyl-3-(piperidin-3-yl)-5- Example 5t 3 1.77 349(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one 6x(S)-3-(piperidin-3-yl)-5- Example 2a 3 1.60 335(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-onehydrochloride 6y 3-(7-methyl-8-oxo-9-(piperidin-4-yl)- Example 5u 3 1.67375 8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrilehydrochloride 6z (S)-3-(3-(piperidin-3-yl)-3H- Example 18e 3 1.68 3.44imidazo[4,5-b]pyridin-5- yl)pyrazolo[1,5-a]pyridine-5- carbonitrilehydrochloride 6aa (S)-3-(2-methyl-3-(piperidin-3-yl)- Example 18f 3 1.72358 3H-imidazo[4,5-b]pyridin-5- yl)pyrazolo[1,5-a]pyridine-5-carbonitrile hydrochloride 6ab 3-(8-oxo-9-(piperidin-4-yl)-8,9- Example1q 1 11.13 361 dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile (1) 6ac 3-(9-(azetidin-3-yl)-7-methyl-8-oxo-Example 5v 3 1.50 347 8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile hydrochloride 6ad(S)-3-(piperidin-3-yl)-5- Example 18i 3 1.65 319(pyrazolo[1,5-a]pyridin-3-yl)-3H- imidazo[4,5-b]pyridine hydrochloride6ae (S)-2-methyl-3-(piperidin-3-yl)-5- Example 21m 3 1.48 333(pyrazolo[1,5-a]pyridin-3-yl)-3H- imidazo[4,5-b]pyridine hydrochloride(1) reaction performed with TFA/CH₂Cl₂ instead of 4M HCl solution indioxane, and washed with with saturated NaHCO₃ aqueous solution.

Example 7(S)-3-(9-(1-(2-Cyanoacetyl)piperidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of the compound obtained in example 6 (45 mg, 0.095 mmol)in anhydrous DMF (3 mL), 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (69 mg,0.38 mmol) and anhydrous TEA (0.09 mL, 0.665 mmol) were added. Thereaction mixture was stirred at room temperature for 18 h, and thesolvent was concentrated off. It was quenched with saturated NaHCO₂aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). Thecombined organic phases were dried over anhydrous Mg₂SO₄, filtered andconcentrated. The crude residue was flash chromatographed on a silicagel flash system (ISCO Rf) using hexanes/acetone mixtures of increasingpolarity as eluent to afford 11.7 mg of the desired compound (29%yield).

LC-MS (method 2): t_(R)=1.93 min; m/z=428 (MH⁺).

Following a similar procedure to that described in example 7, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Compound name Starting material method (min)(MH⁺) 7a (R)-3-(9-(1-(2-cyanoacetyl)piperidin- Example 6a 2 1.93 4283-yl)-8-oxo-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 7b (R)-3-(9-(1-(2-cyanoacetyl)piperidin- Example 6b 2 2.30442 3-yl)-7-methyl-8-oxo-8,9-dihydro- 7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 7c (S)-3-(9-(1-(2-cyanoacetyl)piperidin-Example 6c 2 2.30 442 3-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 7d3-(9-(1-(2-cyanoacetyl)pyrrolidin-3- 3-(7-methyl-8-oxo-9- 2 1.68 428yl)-7-methyl-8-oxo-8,9-dihydro-7H- (pyrrolidin-3-yl)-8,9-purin-2-yl)pyrazolo[1,5-a]pyridine-5- dihydro-7H-purin-2- carbonitrileyl)pyrazolo[1,5- a]pyridine-5- carbonitrile hydrochloride(1) 7e3-(9-((1-(2-cyanoacetyl)piperidin-4- 3-(7-methyl-8-oxo-9- 2 1.80 456yl)methyl)-7-methyl-8-oxo-8,9- (piperidin-4-ylmethyl)-dihydro-7H-purin-2-yl)pyrazolo[1,5- 8,9-dihydro-7H-purin-a]pyridine-5-carbonitrile 2-yl)pyrazolo[1,5- a]pyridine-5- carbonitrilehydrochloride (2) 7f (S)-3-oxo-3-(3-(8-oxo-2- Example 6v 2 2.05 403(pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-9(8H)-yl)piperidin-1-yl)propanenitrile 7g (S)-3-(3-(7-methyl-8-oxo-2- Eample 6u 2 2.58 417(pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-9(8H)-yl)piperidin-1-yl)-3-oxopropanenitrile 7h (S)-3-(3-(1-(2-cyanoacetyl)piperidin- Example 6e 21.64 427 3-yl)-2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 7i(S)-3-(3-(1-methyl-2-oxo-5- Example 6g 5 1.95 416(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile 7j3-(9-(1-(2-cyanoacetyl)azetidin-3- Example 6ac 2 2.10 414yl)-7-methyl-8-oxo-8,9-dihydro-7H- purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 7k (S)-3-(3-(2-(5-methylpyrazolo[1,5- Example 6r 3 1.73 417a]pyridin-3-yl)-8-oxo-7H-purin- 9(8H)-yl)piperidin-1-yl)-3-oxopropanenitrile 7l (S)-3-(3-(1-ethyl-2-oxo-5- Example 6s 4 1.87 430(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile 7m3-oxo-3-(4-(8-oxo-2-(pyrazolo[1,5- Example 6d 4 1.32 403a]pyridin-3-yl)-7H-purin-9(8H)- yl)piperidin-1-yl)propanenitrile 7n(S)-3-(3-(1-(2-cyanoacetyl)piperidin- Example 6f 3 2.02 4413-yl)-1-methyl-2-oxo-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 7o(R)-3-(3-(1-methyl-2-oxo-5- Example 6w 4 1.71 416(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-3(2H)-yl)piperidin-1-yl)-3-oxopropanenitrile 7p (S)-3-oxo-3-(3-(2-oxo-5-Example 6x 3 1.75 402 (pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)- yl)piperidin-1-yl)propanenitrile 7q3-(9-(1-(2-cyanoacetyl)piperidin-4- Example 6y 3 1.82 442yl)-7-methyl-8-oxo-8,9-dihydro-7H- purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 7r (S)-3-(3-(1-(2-cyanoacetyl)piperidin- Example 6z 5 2.20411 3-yl)-3H-imidazo[4,5-b]pyridin-5- yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 7s (S)-3-(3-(1-(2-cyanoacetyl)piperidin- Example 6aa 5 2.09425 3-yl)-2-methyl-3H-imidazo[4,5- b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 7t (S)-3-(3-(2-methyl-5-(pyrazolo[1,5- Example6ae 3 1.85 400 a]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)-3- oxopropanenitrile 7u(S)-3-oxo-3-(3-(5-(pyrazolo[1,5- Example 6ad 3 1.77 386a]pyridin-3-yl)-3H-imidazo[4,5- b]pyridin-3-yl)piperidin-1-yl)propanenitrile (1)obtained as example 6, but using tert-butyl3-aminopyrrolidine-1-carboxylate as starting material. (2) obtained asexample 6, but using tert-butyl 4-(aminomethyl)piperidine-1-carboxylateas starting material.

Example 8(S)-3-(9-(1-Acetylpiperidin-3yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of the compound obtained in example 6 (31 mg, 0.063 mmol)in anhydrous DMF (3 mL), acetic anhydride (0.007 mL, 0.08 mmol) andanhydrous TEA (0.02 mL, 0.127 mmol) were added. The reaction mixture wasstirred at room temperature for 18 h, and the solvent was concentratedoff. It was quenched with saturated NaHCO₃ aqueous solution (15 mL) andextracted with EtOAc (3×15 mL). The combined organic phases were driedover anhydrous Mg₂SO₄, filtered and concentrated. The crude residue wasflash chromatographed on a silica gel flash system (ISCO Rf) usinghexanes/acetone mixtures of increasing polarity as eluent to afford 14.5mg of the desired compound (57% yield).

LC-MS (method 2): t_(R)=1.8 min; m/z=403 (MH⁺).

Following a similar procedure to that described in example 8, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Compound name Starting material method (min)(MH⁺) 8a (S)-9-(1-acetylpiperidin-3-yl)-2- Example 6v 2 1.55 378(pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one 8b3-(9-(1-acetylpiperidin-4-yl)-8-oxo- Example 6ab 1 13.31 4038,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 8c9-(1-acetylpiperidin-4-yl)-2- Example 6d 4 1.30 378(pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one 8d(S)-3-(1-isobutyrylpiperidin-3-yl)-5- Example 6x 3 2.00 405(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one (1) 8e(S)-3-(9-(1-acetylpiperidin-3-yl)-7- Example 6c 3 1.88 417methyl-8-oxo-8,9-dihydro-7H-purin- 2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 8f (S)-3-(1-acetylpiperidin-3-yl)-5- Example 6x 3 1.72 377(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one 8g3-(9-(1-acetylpiperidin-4-yl)-7- Example 6y 3 1.78 417methyl-8-oxo-8,9-dihydro-7H-purin- 2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 8h 3-(9-(1-acetylazetidin-3-yl)-7- Example 6ac 3 1.62 389methyl-8-oxo-8,9-dihydro-7H-purin- 2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile (1) using isobutyryl chloride instead of acetic anhydrideas starting material.

Example 9(S)-3-(9-(1-(Methylsulfonyl)piperidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of the compound obtained in example 6 (31 mg, 0.063 mmol)in anhydrous DMF (3 m L), methanesulphonic anhydride (13 mg, 0.08 mmol)and anhydrous TEA (0.02 mL, 0.127 mmol) were added. The reaction mixturewas stirred at room temperature for 18 h, and the solvent wasconcentrated off. It was quenched with saturated NaHCO₃ aqueous solution(15 mL) and extracted with EtOAc (3×15 mL). The combined organic phaseswere dried over anhydrous Mg₂SO₄, filtered and concentrated. The cruderesidue was chromatographed on a silica gel flash system (ISCO Rf) usinghexanes/acetone mixtures of increasing polarity as eluent to afford 14.3mg of the titled compound (52% yield).

LC-MS (method 1 PCB): t_(R)=2.08 min; m/z=439 (MH⁺).

Following a similar procedure to that described in example 9, but usingthe corresponding starting materials, the following compounds wereobtained:

HPLC t_(R) m/z Example Compound name Starting material method (min)(MH⁺) 9a (S)-9-(1-(methylsulfonyl)piperidin-3- Example 6v and 2 1.70 414yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)- methanesulphonyl 7H-purin-8(9H)-onechloride 9b (S)-3-(8-oxo-9-(1- Example 6 and 5 2.48 467(propylsulfonyl)piperidin-3-yl)-8,9- propane-1-sulfonyldihydro-7H-purin-2-yl)pyrazolo[1,5- chloride a]pyridine-5-carbonitrile9c (S)-3-(8-oxo-9-(1-(2,2,2- Example 6 and 2,2,2- 5 2.55 507trifluoroethylsulfonyl)piperidin-3-yl)- trifluoroethanesulfonyl8,9-dihydro-7H-purin-2- chloride yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 9d (S)-3-(9-(1- Example 6 and 2- 3 2.70 481(isobutylsulfonyl)piperidin-3-yl)-8- methylpropane-1-oxo-8,9-dihydro-7H-purin-2- sulfonyl chlorideyl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9e (S)-3-(8-oxo-9-(1-(3,3,3-Example 6 and 3,3,3- 3 2.70 521 trifluoropropylsulfonyl)piperidin-3-trifluoropropane-1- yl)-8,9-dihydro-7H-purin-2- sulfonyl chlorideyl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9f (S)-1-methyl-3-(1- Example6g and 4 1.81 427 (methylsulfonyl)piperidin-3-yl)-5- methanesulphonyl(pyrazolo[1,5-a]pyridin-3-yl)-1H- chlorideimidazo[4,5-b]pyridin-2(3H)-one 9g (S)-2-(5-methylpyrazolo[1,5- Example6r and 3 1.87 428 a]pyridin-3-yl)-9-(1- methanesulphonyl(methylsulfonyl)piperidin-3-yl)-7H- chloride purin-8(9H)-one 9h7-(2-oxopropyl)-9-(1-(2- Example 6d and 1- 4 1.66 448oxopropyl)piperidin-4-yl)-2- chloropropan-2-one(pyrazolo[1,5-a]pyridin-3-yl)-7H- purin-8(9H)-one 9i9-(1-acetylpiperidin-4-yl)-7-methyl- Example 6t and 4 1.42 3922-(pyrazolo[1,5-a]pyridin-3-yl)-7H- acetyl choride purin-8(9H)-one 9j(S)-3-(3-(1-isobutyrylpiperidin-3-yl)- Example 6e and 5 2.52 4302-oxo-2,3-dihydro-1H-imidazo[4,5- isobutyryl chlorideb]pyridin-5-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 9k(S)-3-(3-(1-(methylsulfonyl)piperidin- Example 6e and 3 1.92 4383-yl)-2-oxo-2,3-dihydro-1H- methanesulphonyl imidazo[4,5-b]pyridin-5-chloride yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9l(S)-3-(7-methyl-9-(1- Example 6c and 3 2.05 453(methylsulfonyl)piperidin-3-yl)-8- methanesulphonyloxo-8,9-dihydro-7H-purin-2- chloride yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 9m (S)-3-(9-(1-(ethylsulfonyl)piperidin- Example 6 and 31.90 453 3-yl)-8-oxo-8,9-dihydro-7H-purin-2- ethylsulphonylyl)pyrazolo[1,5-a]pyridine-5- chloride carbonitrile 9n(S)-3-(9-(1-isobutyrylpiperidin-3-yl)- Example 6 and 3 1.95 4318-oxo-8,9-dihydro-7H-purin-2- isobutyryl chlorideyl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9o 3-(7-methyl-9-(1- Example6y and 3 1.95 453 (methylsulfonyl)piperidin-4-yl)-8- methanesulphonyloxo-8,9-dihydro-7H-purin-2- chloride yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 9p 3-(9-(1-(methylsulfonyl)piperidin-4- Example 6ab and 114.06 439 yl)-8-oxo-8,9-dihydro-7H-purin-2- methanesulphonylyl)pyrazolo[1,5-a]pyridine-5- chloride carbonitrile 9q(S)-3-(1-(methylsulfonyl)piperidin-3- Example 6x and 3 1.85 413yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)- methanesulphonyl1H-imidazo[4,5-b]pyridin-2(3H)-one chloride 9r 3-(7-methyl-9-(1- Example6ac and 3 2.30 425 (methylsulfonyl)azetidin-3-yl)-8-oxo-methanesulphonyl 8,9-dihydro-7H-purin-2- chlorideyl)pyrazolo[1,5-a]pyridine-5- carbonitrile 9s(S)-3-(3-(1-acetylpiperidin-3-yl)-2- Example 6e and 5 2.25 402oxo-2,3-dihydro-1H-imidazo[4,5- acetyl chlorideb]pyridin-5-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 9t(S)-3-(1-(2-methoxyacetyl)piperidin- Example 6g and 2- 4 1.68 4213-yl)-1-methyl-5-(pyrazolo[1,5- methoxyacetyla]pyridin-3-yl)-1H-imidazo[4,5- chloride b]pyridin-2(3H)-one 9u(S)-1-methyl-5-(pyrazolo[1,5- Example 6g and 4 2.17 495a]pyridin-3-yl)-3-(1-(2,2,2- 2,2,2-trifluoroethylsulfonyl)piperidin-3-yl)- trifluoroethanesulfonyl1H-imidazo[4,5-b]pyridin-2(3H)-one chloride

Example 10(S)-3-(9-(1-(2-Dimethylamino)acetyl)piperidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of N,N-dimethylglicine (10 mg, 0.095 mmol) in anhydrousDMF (2 mL), HOBt.H₂O was added. After 15 min, EDC.HCl (24 mg, 0.126mmol) and the compound obtained in example 6 (31 mg, 0.063 mmol) wereadded. The reaction mixture was stirred at room temperature for 2.5 hand the solvent was concentrated off. It was quenched with saturatedNaHCO₃ aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). Thecombined organic phases were dried over anhydrous Mg₂SO₄, filtered andconcentrated. The crude residue was chromatographed on a silica gelflash system (ISCO Rf) using hexanes/acetone mixtures of increasingpolarity as eluent to afford 8.2 mg of the titled compound (29% yield).

LC-MS (method 3): t_(R)=1.67 min; m/z=446 (MH⁺).

Following a similar procedure to that described in example 10, but usingthe corresponding starting material, the following compound wasobtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 10a(S)-3-(9-(1-(2- Example 6 and 3 1.52 419hydroxyacetyl)piperidin-3-yl)-8-oxo- glicolic acid8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 10b(S)-3-(9-(1-(2-hydroxy-2- Example 6 and 2- 3 1.75 447methylpropanoyl)piperidin-3-yl)-8- hydroxy-2-oxo-8,9-dihydro-7H-purin-2- methylpropanoicyl)pyrazolo[1,5-a]pyridine-5- acid carbonitrile 10c3-(8-oxo-9-((S)-1-((S)- Example 6 and (S)- 3 1.75 459 tetrahydrofuran-2-tetrahydrofuran-2- carbonyl)piperidin-3-yl)-8,9-dihydro- carboxylic acid7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 10d(S)-3-(9-(1-(2- Example 6 and 2- 3 1.65 433methoxyacetyl)piperidin-3-yl)-8- methoxyacetic acidoxo-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile10e (S)-3-(9-(1-(2- Example 6 and 2- 3 2.20 459ethylbutanoyl)piperidin-3-yl)-8-oxo- ethylbutanoic acid8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 10f(S)-3-(9-(1-(2-(3-methylisoxazol-5- Example 6 and 2-(3- 3 1.82 484yl)acetyl)piperidin-3-yl)-8-oxo-8,9- methylisoxazol-5-dihydro-7H-purin-2-yl)pyrazolo[1,5- yl)acetic acida]pyridine-5-carbonitrile 10g 3-(9-((S)-1-((S)-2- Example 6 and (S)- 52.23 447 methoxypropanoyl)piperidin-3-yl)-8- 2-methoxypropanoicoxo-8,9-dihydro-7H-purin-2- acid yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 10h (S)-3-(8-oxo-9-(1-(3,3,3- Example 6 and 3 1.97 471trifluoropropanoyl)piperidin-3-yl)- 3,3,3- 8,9-dihydro-7H-purin-2-trifluoropropanoic yl)pyrazolo[1,5-a]pyridine-5- acid carbonitrile 10i(S)-2-(5-methylpyrazolo[1,5- Example 6r and 3 1.85 406a]pyridin-3-yl)-9-(1- propionic acid propionylpiperidin-3-yl)-7H-purin-8(9H)-one 10j (S)-9-(1-(2-methoxyacetyl)piperidin- Example 6r and 2- 31.72 422 3-yl)-2-(5-methylpyrazolo[1,5- methoxyacetic acida]pyridin-3-yl)-7H-purin-8(9H)-one 10k (S)-7-(2-methoxyacetyl)-9-(1-(2-Example 6r and 2- 3 2.13 494 methoxyacetyl)piperidin-3-yl)-2-(5-methoxyacetic acid methylpyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-one 10l (S)-9-(1-acetylpiperidin-3-yl)-2-(5- Example 6rand 3 1.70 392 methylpyrazolo[1,5-a]pyridin-3-yl)- acetic acid7H-purin-8(9H)-one 10m (S)-9-(1-(2-hydroxyacetyl)piperidin- Example 6rand 2- 3 1.60 408 3-yl)-2-(5-methylpyrazolo[1,5- hydroxyacetic acida]pyridin-3-yl)-7H-purin-8(9H)-one 10n (S)-3-(9-(1- Example 6 and 3 1.88429 (cyclopropanecarbonyl)piperidin-3- cyclopropanecarboxylicyl)-8-oxo-8,9-dihydro-7H-purin-2- acid yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 10o (S)-3-(1-(2-hydroxy-2- Example 6g and 2- 4 1.76 435methylpropanoyl)piperidin-3-yl)-1- hydroxy-2-methyl-5-(pyrazolo[1,5-a]pyridin-3- methylpropanoicyl)-1H-imidazo[4,5-b]pyridin-2(3H)- acid one 10p(S)-3-(1-(2-hydroxyacetyl)piperidin- Examle 6g and 2- 4 1.59 4073-yl)-1-methyl-5-(pyrazolo[1,5- hydroxyacetic acida]pyridin-3-yl)-1H-imidazo[4,5- b]pyridin-2(3H)-one 10q (S)-3-(1-(2-Examle 6g and N,N- 4 1.65 434 (dimethylamino)acetyl)piperidin-3-dimethylglicine yl)-1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5- b]pyridin-2(3H)-one 10r1-methyl-5-(pyrazolo[1,5-a]pyridin- Examle 6g and (S)- 4 1.76 4473-yl)-3-((S)-1-((S)-tetrahydrofuran- tetrahydrofuran-2-2-carbonyl)piperidin-3-yl)-1H- carboxylic acidimidazo[4,5-b]pyridin-2(3H)-one 10s (S)-1-methyl-5-(pyrazolo[1,5-Example 6g and 4 1.99 459 a]pyridin-3-yl)-3-(1-(3,3,3- 3,3,3-trifluoropropanoyl)piperidin-3-yl)- trifluoropropanoic1H-imidazo[4,5-b]pyridin-2(3H)-one acid

Example 11(S)-3-(2-(5-Cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N,N-dimethylpiperidine-1-sulfonamide

To a solution of the compound obtained in example 6 (110 mg, 0.22 mmol)in anhydrous DMF (3 mL), N,N-dimethylsulfamoyl chloride (0.03 mL, 0.27mmol) and anhydrous TEA (0.13 mL, 0.90 mmol) were added. The reactionmixture was stirred at room temperature for 18 h, and the solvent wasconcentrated off. It was quenched with saturated NaHCO₃ aqueous solution(15 mL) and extracted with EtOAc (3×15 mL). The combined organic phaseswere dried over anhydrous Mg₂SO₄, filtered and concentrated. The cruderesidue was chromatographed on a silica gel flash system (ISCO Rf) usinghexanes/acetone mixtures of increasing polarity as eluent to afford 39.2mg of the titled compound (38% yield).

LC-MS (method 1): t_(R)=1.95 min; m/z=468 (MH⁺).

Following a similar procedure to that described in example 11, but usingthe corresponding starting materials, the following compound wasobtained:

Starting HPLC tR m/z Example Name Materials method (min) (MH+) 11a(S)—N,N-dimethyl-3- Example 4 2.05 456 (1-methyl-2-oxo-5- 6g(pyrazolo[1,5- a]pyridin-3-yl)- 1H-imidazo[4,5- b]pyridin-3(2H)-yl)piperidine-1- sulfonamide

Example 123-(9-(1-Acetylpyrrolidin-3-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrilea) tert-Butyl3-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate

Following a similar procedure to that described in example 1, but usingtert-butyl 3-aminopyrrolidine-1-carboxylate instead oftetrahydro-2H-pyran-4-amine, the desired compound was obtained.

b) tert-Butyl3-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)-7-methyl-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate

Following a similar procedure to that described in example 5, but usingthe compound obtained in previous section as starting material, thedesired compound was obtained (25% yield).

c)3-Methyl-8-oxo-9-(pyrrolidin-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrilehydrochloride

Following a similar procedure to that described in example 6, but usingthe compound obtained in previous section as starting material, thedesired compound was obtained (100% yield).

d) Title Compound

Following a similar procedure to that described in example 8, but usingthe compound obtained in previous section as starting material, thedesired compound was obtained (22% yield).

LC-MS (method 2): t_(R)=1.67 min; m/z=403 (MH⁺).

Example 13

3-(7-Methyl-9-(1-methylsulfonyl)pyrrolidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Following a similar procedure to that described in example 9, but usingthe compound obtained in example 12 section c as starting material, thedesired compound was obtained (15% yield),

LC-MS (method 2): t_(R)=1.83 min; m/z=439 (MH⁺).

Following a similar procedure to that described in example 13, but usingthe corresponding starting materials, the following compounds wereobtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 13a(S)-3-(7-methyl-9-(1- Example 6h 3 2.35 439(methylsulfonyl)pyrrolidin-3-yl)-8- oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 13b (R)-3-(7-methyl-9-(1-Example 6i 3 2.35 439 (methylsulfonyl)pyrrolidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2- yl)pyrazolo[1,5-a]pyridine-5- carbonitrile13c (S)-9-(1-(methylsulfonyl)pyrrolidin- Example 6j 3 1.53 4003-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)- 7H-purin-8(9H)-one 13d(S)-7-methyl-9-(1- Example 6k 3 1.77 414(methylsulfonyl)pyrrolidin-3-yl)-2- (pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-one 13e (S)-3-(9-(1- Example 6l 3 1.63 425(methylsulfonyl)pyrrolidin-3-yl)-8- oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 13f (R)-1-methyl-3-(1-Example 6m 3 1.90 413 (methylsulfonyl)pyrrolidin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one 13g(R)-3-(1-(methylsulfonyl)pyrrolidin- Example 6n 3 1.72 3993-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one 13h (R)-3-(9-(1- Example 6o 3 1.62425 (methylsulfonyl)pyrrolidin-3-yl)-8- oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 13i(S)-3-(1-(methylsulfonyl)pyrrolidin- Example 6p 3 1.72 3993-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one 13j (S)-1-methyl-3-(1- Example 6q 31.92 413 (methylsulfonyl)pyrrolidin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H- imidazo[4,5-b]pyridin-2(3H)-one 13k(S)-7-methyl-9-(1- Example 6u 3 1.93 428(methylsulfonyl)piperidin-3-yl)-2- (pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-one

Example 14

(2R)-2-[2-(5-Cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]propanoicacid

To a suspension of example 1a (65 mg, 018 mmol) in dioxane (1.6 mL) andH₂O (0.8 mL) at 0° C., LiOH.H₂O (15 mg, 0.36 mmol) was added. Thereaction mixture was stirred at 0° C. for 1 h and room temperature for26 h. The pH of the solution was adjusted to 5 by adding 10 % HClaqueous solution. The solvent was removed under vacuum and the resultingsolid was suspended in Et₂O (10 mL) and concentrated. The resultingsolid was washed with water (2×5 mL), hexanes (3 mL) and Et₂O (2×5 mL)to afford 57 mg of the desired product (91%).

LC-MS (method 1): t_(R)=13.59 min; m/z=350 (MH⁺).

Following a similar procedure to that described in example 14, but usingthe corresponding starting materials, the following compounds wereobtained:

Starting HPLC t_(R) m/z Example Name Material method (min) (MH⁺) 14a(2S)-2-[2-(5- Example 1i 1 13.59 350 Cyanopyrazolo[1,5-a]pyridin-3-yl)-8- oxo-7,8-dihydro- 9H-purin-9- yl]propanoic acid 14b(S)-2-(8-oxo-2- Example 3e 3 1.10 325 (pyrazolo[1,5- a]pyridin-3-yl)-7H-purin-9(8H)- yl)propanoic acid

Example 15(2R)-2-[2-(5-Cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-N-(2,2,2-trifluoroethyl)propanamide

To a solution of HOBt.H₂O (31 mg, 0.20 mmol) and TEA (0.068 mL, 0.49mmol) in THF (1 mL), example 14 (70 mg, 0.20 mmol) was added. After 15min, EDC.HCl (40 mg, 0.21 mmol) and 2,2,2-trifluoroethylaminehydrochloride (14.6 mg, 0.11 mmol) were added and the resulting mixturewas stirred at room temperature for 3.5 days. Then, it was quenched withH₂O (5 mL) and extracted with EtOAc (3×15 mL). The combined organicphases ware dried over anhydrous Na₂SO₄, filtered and concentrated. Thecrude product thus obtained was chromatographed over silica gel usingMeOH/CH₂Cl₂ mixtures of increasing polarity as eluent, to afford 18 mgof the desired compound (50% yield).

LC-MS (method 1): t_(R)=15.34 min; m/z=431 (MH⁺).

Following a similar procedure to that described in example 15, but usingthe corresponding starting material, the following compound wasobtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 15a(2R)-(2-(5-cyanopyrazolo[1,5- Example 14 and N- 1 13.62 363a]pyridin-3-yl)-8-oxo-7H-purin- methylamine9(8H)-yl)-N-methylpropanamide 15b (2S)-2-[2-(5-cyanopyrazolo[1,5-(2S)-2-[2-(5- 3 2.08 459 a]pyridin-3-yl)-8-oxo-7,8-dihydro-cyanopyrazolo[1,5- 9H-purin-9-yl]-3-methyl-N-(2,2,2-a]pyridin-3-yl)-8-oxo- trifluoroethyl)butanamide 7,8-dihydro-9H-purin-9-yl)-3-methylbutanoic acid (1) and 2,2,2- trifluoroethylamine 15c(R)-2-(2-(5-cyanopyrazolo[1,5- Example 14 and 2- 3 1.35 393a]pyridin-3-yl)-8-oxo-7H-purin- aminoethanol 9(8H)-yl)-N-(2-hydroxyethyl)propanamide 15d (R)-2-(2-(5-cyanopyrazolo[1,5- Example 14and 3 1.75 403 a]pyridin-3-yl)-8-oxo-7H-purin- cyclopropylmethanamine9(8H)-yl)-N- (cyclopropylmethyl)propanamide 15e(R)-2-(2-(5-cyanopyrazolo[1,5- Example 14 and 3 1.48 420a]pyridin-3-yl)-8-oxo-7H-purin- N1,N1- 9(8H)-yl)-N-(2-dimethylethane-1,2- (dimethylamino)ethyl)propanamide diamine 15f(R)-2-(2-(5-cyanopyrazolo[1,5- Example 14 and N- 3 1.57 377a]pyridin-3-yl)-8-oxo-7H-purin- ethylamine 9(8H)-yl)-N-ethylpropanamide15g (R)-2-(2-(5-cyanopyrazolo[1,5- Example 14 and N- 3 1.70 391a]pyridin-3-yl)-8-oxo-7H-purin- isopropylamine9(8H)-yl)-N-isopropylpropanamide 15h (R)-2-(2-(5-cyanopyrazolo[1,5-Example 14 and N,N- 3 1.53 377 a]pyridin-3-yl)-8-oxo-7H-purin-dimethylamine 9(8H)-yl)-N,N-dimethylpropanamide 15i(S)-2-(2-(5-cyanopyrazolo[1,5- Example 14a and 3 1.72 431a]pyridin-3-yl)-8-oxo-7H-purin- 2,2,2- 9(8H)-yl)-N-(2,2,2-trifluoroethylamine trifluoroethyl)propanamide 15j(S)-N-methyl-2-(8-oxo-2- Example 14b and N- 3 1.35 338(pyrazolo[1,5-a]pyridin-3-yl)-7H- methylamine purin-9(8H)-yl)propanamide15k (S)-N,N-dimethyl-2-(8-oxo-2- Example 14b and N,N- 5 1.90 352(pyrazolo[1,5-a]pyridin-3-yl)-7H- dimethylaminepurin-9(8H)-yl)propanamide (1) Obtained as example 14 but usingHCl/Dioxane 4M/H₂O (1:1) instead of LiOH•H2O, and L-Valine methyl esterhydrochloride as starting material.

Example 163-(7-(2-Methoxyethyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of example 1 (50 mg, 0.14 mmol) in DMF (8 mL), 55-65% NaHdispersion in mineral oil (6 mg, 0.15 mmol) was added and the resultingsolution was stirred at room temperature for 10 min. Then 2-bromoethylmethyl ether (0.032 mL, 0.34 mmol) was added and the reaction mixturewas stirred at 50° C. for 14.5 h. The reaction mixture was quenched withH₂O (10 mL) and extracted with EtOAc (3×10 mL). The combined organicphases were dried over anhydrous Na₂SO₄, filtered and concentrated. Thecrude product thus obtained was chromatographed over silica gel usingEtOAc/hexanes mixtures of increasing polarity as eluent, to afford 36 mgof the desired compound (62% yield).

LC-MS (method 1): t_(R)=16.17 min; m/z=420 (MH⁺).

Following a similar procedure to that described in example 16, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 16a(S)-3-(9-(1-(2- 2-bromo-N,N- 2 1.95 499cyanoacetyl)piperidin-3-yl)-7-(2- dimethylethanamine(dimethylamino)ethyl)-8-oxo-8,9- and example 1b (1)dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 16b(S)-3-(7-(2-(dimethylamino)ethyl)-8- 2-bromo-N,N- 2 1.83 432oxo-9-(piperidin-3-yl)-8,9-dihydro- dimethylethanamine7H-purin-2-yl)pyrazolo[1,5- and example 1b (2) a]pyridine-5-carbonitrile16c 7-(2-(dimethylamino)ethyl)-2- 2-bromo-N,N- 2 1.921 408(pyrazolo[1,5-a]pyridin-3-yl)-9- dimethylethanamine(tetrahydro-2H-pyran-4-yl)-7H- and example 3 purin-8(9H)-one) 16d3-(7-(2-(dimethylamino)ethyl)-8- 2-bromo-N,N- 1 14.79 433oxo-9-(tetrahydro-2H-pyran-4-yl)- dimethylethanamine8,9-dihydro-7H-purin-2- and example 1 yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 16e 3-(7-(2-(dimethylamino)ethyl)-9-(8- 2-bromo-N,N- 4 2.12499 fluorochroman-4-yl)-8-oxo-8,9- dimethylethanaminedihydro-7H-purin-2-yl)pyrazolo[1,5- and example 1pa]pyridine-5-carbonitrile 16f 3-(9-(8-fluorochroman-4-yl)-7-(2-2-bromoethyl methyl 4 2.20 486 methoxyethyl)-8-oxo-8,9-dihydro- etherand example 7H-purin-2-yl)pyrazolo[1,5- 1p a]pyridine-5-carbonitrile 16g3-(9-(8-fluorochroman-4-yl)-7-(3- 3-bromopropan-1-ol 4 1.96 486hydroxypropyl)-8-oxo-8,9-dihydro- and example 1p7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 16h(S)-3-(3-(1-(2- 2-bromo-N,N- 4 1.73 473 (dimethylamino)ethyl)-2-oxo-5-dimethylethanamine (pyrazolo[1,5-a]pyridin-3-yl)-1H- and example 2a (1)imidazo[4,5-b]pyridin-3(2H)- yl)piperidin-1-yl)-3- oxopropanenitrile 16i(S)-3-(3-(1-(2-methoxyethyl)-2-oxo- 2-bromoethyl methyl 4 1.82 4605-(pyrazolo[1,5-a]pyridin-3-yl)-1H- ether and exampleimidazo[4,5-b]pyridin-3(2H)- 2a (1) yl)piperidin-1-yl)-3-oxopropanenitrile 16j (S)-3-(3-(1-(cyclopropylmethyl)-2-(bromomethyl)cyclo 4 2.08 456 oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-propane and 1H-imidazo[4,5-b]pyridin-3(2H)- example 2a (1)yl)piperidin-1-yl)-3- oxopropanenitrile (1) followew by a similarprocedure to that described in example 6 (tert-butoxtcarbonyl cleavage)and 7 (amide formation). (2) followew by tert-butoxycarbonyl cleavage asexample 6

Example 173(7-(2-Hydroxyethyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrilea)3-(7-(2-tert-Butyldimethylsilyloxy)ethyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of example 1 (50 mg, 0.14 mmol) in DMF (8 mL), 55-65% NaHdispersion in mineral oil (6 mg, 0.15 mmol) was added. The resultingsolution was stirred at room temperature for 10 min. Then(2-bromoethoxy)-tert-butyldimethylsilane (0.074 mL, 0.34 mmol) was addedand the reaction was stirred at 50° C. for 14.5 h. The reaction mixturewas quenched with H₂O (10 mL) and extracted with EtOAc (3×10 mL). Thecombined organic phases were dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product thus obtained was chromatographed oversilica gel using hexanes/EtOAc mixtures of increasing polarity aseluent, to afford 55 mg of the desired compound (76% yield).

b) Title Compound

To a solution of the compound obtained in the previous section (55 mg,0.10 mmol) in THF (5 mL) 1 M TBAF solution in THF (0.14 mL, 0.14 mmol)was added and the resulting solution was stirred at room temperature for1 h. The reaction mixture was quenched with H₂O (10 mL) and extractedwith EtOAc (3×10 mL) and CH₂Cl₂ (2×10 mL). The combined organic phaseswere dried over anhydrous Na₂SO₄, filtered and concentrated. The crudeproduct thus obtained was chromatographed over silica gel usingMeOH/EtOAc mixtures of increasing polarity as eluent, to afford 39 mg ofthe desired compound (91% yield).

LC-MS (method 1): t_(R)=14.13 min; m/z=406 (MH⁺).

Following a similar procedure to that described in example 17, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 17a(S)-3-(9-(1-(2- Example 1b (1) 1 1.68 472cyanoacetyl)piperidin-3-yl)-7-(2- hydroxyethyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile 17b(S)-3-(7-(2-hydroxyethyl)-8-oxo-9- Example 1b (2) 1 1.55 405(piperidin-3-yl)-8,9-dihydro-7H- purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile hydrochloride 17c 3-(9-(8-fluorochroman-4-yl)-7-(2- Example1p 1 15.99 472 hydroxyethyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5- a]pyridine-5-carbonitrile (1) Followed by asimilar procedure to that described in example 6 (tert-butoxtcarbonylcleavage) and 7 (amide formation). (2) Followed by tert-butoxycarbonylcleavage as example 6

Example 183-(9-Tetrahydro-2H-pyran-4-yl-9H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a suspension of the compound obtained in example 1 section d (100 mg,0.30 mmol) in EtOH (1 mL), PTSA monohydrate (5.7 mg, 0.03 mmol) andtriethylorthoformate (1 mL) were added. The reaction mixture was heatedin a CEM Explorer microwave oven at 123° C. and 270 W for 30 min. Then,it was evaporated to dryness. The crude product thus obtained waschromatographed over silica gel using MeOH/EtOAc mixtures of increasingpolarity as eluent, to afford 81 mg of the desired compound (79% yield).

LC-MS (method 1): t_(R)=14.56 min; m/z=346 (MH⁺).

Following a similar procedure to that described in example 18, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 18a3-(8-methyl-9-tetrahydro-2H-pyran- Example 1 section d 1 14.77 3604-yl-9H-purin-2-yl)pyrazolo[1,5- and a]pyridine-5-carbonitriletriethylorthoacetate 18b 3-(9-(4,4-difluorocyclohexyl)-8-triethylorthoacetate 2 2.17 394 methyl-9H-purin-2-yl)pyrazolo[1,5- and3-(5-amino-4-(4,4- a]pyridine-5-carbonitriledifluorocyclohexylamino)pyrimidin- 2- yl)pyrazolo[1,5- a]pyridine-5-carbonitrile (1) 18c 3-(9-(1,1-dioxotetrahydrothien-3-yl)-triethylorthoacetate 2 1.65 394 8-methyl-9H-purin-2- and3-(5-amino-4-(1,1- yl)pyrazolo[1,5-a]pyridine-5- dioxotetrahydrothien-carbonitrile 3-yl)aminopyrimidin-2- yl)pyrazolo[1,5- a]pyridine-5-carbonitrile (2) 18d 5-(pyrazolo[1,5-a]pyridin-3-yl)-3- Referenceexample 2g 3 1.85 320 (tetrahydro-2H-pyran-4-yl)-3H- andimidazo[4,5-b]pyridine triethylorthoformate 18e (S)-tert-butyl 3-(5-(5-Reference example 2h 3 2.33 444 cyanopyrazolo[1,5-a]pyridin-3-yl)- and3H-imidazo[4,5-b]pyridin-3- triethylorthoformateyl)piperidine-1-carboxylate 18f (S)-tert-butyl 3-(5-(5- Referenceexample 2h 3 2.57 458 cyanopyrazolo[1,5-a]pyridin-3-yl)-2- andmethyl-3H-imidazo[4,5-b]pyridin-3- triethylorthoacetateyl)piperidine-1-carboxylate 18g 2-methyl-5-(pyrazolo[1,5-a]pyridin-Reference example 2g 3 1.92 334 3-yl)-3-(tetrahydro-2H-pyran-4-yl)- and3H-imidazo[4,5-b]pyridine triethylorthoacetate 18h3-(9-(trans-4-hydroxycyclohexyl)-8- Reference example 2j 3 1.70 374methyl-9H-purin-2-yl)pyrazolo[1,5- and a]pyridine-5-carbonitriletriethylorthoacetate 18i (S)-tert-butyl 3-(5-(pyrazolo[1,5- Referenceexample 2d 3 1.77 386 a]pyridin-3-yl)-3H-imidazo[4,5- andb]pyridin-3-yl)piperidine-1- triethylorthoformate carboxylate (1)obtained in example 1e section d (2) obtained in example 1f section d

Example 193-(3-(Tetrahydro-2H-pyran-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a suspension of the compound obtained in example 2 section d (33.6mg, 0.1 mmol) in EtOH (1.5 mL), citric acid (2 mg, 0.1 mmol) andtriethyl orthoformate (340 μL, 2 mmol) were added. The reaction mixturewas heated in a CEM Explorer microwave oven at 145° C. and 270 W for 2.5hours. The crude residue was cromategraphed on a silica gel flash system(ISCO Rf) using hexanes/acetone mixtures of increasing polarity aseluent to afford 14.2 mg of the desired product (41% yield).

LC-MS (method 3): t_(R)=1.76 min; m/z=345 (MH⁺).

Following a similar procedure to that described in example 19, but usingthe corresponding starting material, the following compound wasobtained:

Starting HPLC t_(R) m/z Example Name Material method (min) (MH⁺) 19a(S)-3-(3-(1- Reference 5 2.22 386 acetylpiperidin-3- example 2fyl)-3H-imidazo- [4,5-b]pyridin- 5-yl)pyrazolo- [1,5-a]pyridine-5-carbonitrile

Example 203-(2-Methyl-3-(tetrahydro-2H-pyran-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of the compound obtained in example 2 section d (56.4 mg,0.169 mmol) in EtOH (1.5 mL), PTSA monohydrate (3.21 mg, 0.017 mmol) andtriethyl orthoacetate (547 mg, 3.37 mmol) were added. The reactionmixture was heated in a CEM Explorer microwave oven at 145° C. and 270 Wfor 2.5 hours. The crude residue was cromategraphed on a silica gelflash system (ISCO Rf) using CH₂Cl₂/MeOH mixtures of increasingpolarity, a eluent to afford the desired product (15% yield).

LC-MS (method 3): t_(R)=1.79 min; m/z=359.5 (MH⁺).

Example 213-(8-(1-Methyl-1H-imidazol-2-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of the compound obtained in example 1 section d (100 mg,0.30 mmol) in AcOH (0.025 mL) and DMA (2.5 mL),1-methyl-1H-imidazole-2-carbaldehyde (46 mg, 0.42 mmol) was added. Thereaction mixture was stirred in a sealed tube at 140° C. for 19 h. Thecrude mixture was quenched with H₂O (10 mL), extracted with EtOAc (3×10mL) and the combined organic phases were dried over anhydrous Na₂SO₄,filtered and concentrated. The crude product thus obtained waschromatographed over silica gel using hexanes/EtOAc mixtures ofincreasing polarity as eluent, to afford 40 mg of the desired compound(31% yield).

LC-MS (method 1): t_(R)=16.436 min; m/z=426 (MH⁺).

Following a similar procedure to that described in example 21, but usingthe corresponding starting material, the following compound wasobtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 21a3-(8-(pyrimidin-5-yl)-9-(tetrahydro- Example 1 section d 4 1.67 4242H-pyran-4-yl)-9H-purin-2- and pyrimidine-5-yl)pyrazolo[1,5-a]pyridine-5- carbaldehyde carbonitrile 21b3-(9-(8-fluorochroman-4-yl)-8- Reference example 1 16.34 490(pyrimidin-5-yl)-9H-purin-2- 2e and pyrimidine-5-yl)pyrazolo[1,5-a]pyridine-5- carbaldehyde carbonitrile 21c3-(9-(8-fluorochroman-4-yl)-8-(1- Reference example 1 18.4 492methyl-1H-imidazol-2-yl)-9H-purin- 2e and 1-methyl-1H-2-yl)pyrazolo[1,5-a]pyridine-5- imidazole-2- carbonitrile carbaldehyde21d 2-(pyrazolo[1,5-a]pyridin-3-yl)-8- Reference example 3 2.15 386(1H-pyrrol-2-yl)-9-(tetrahydro-2H- 2c and 1H-pyrrole-2-pyran-4-yl)-9H-purine carbaldehyde 21e 8-(5-methylthiophen-2-yl)-2-Reference example 3 2.52 417 (pyrazolo[1,5-a]pyridin-3-yl)-9- 2c and 5-(tetrahydro-2H-pyran-4-yl)-9H- methylthiophene-2- purine carbaldehyde21f 8-(1-methyl-1H-imidazol-2-yl)-2- Reference example 3 2.05 401(pyrazolo[1,5-a]pyridin-3-yl)-9- 2c and 1-methyl-1H-(tetrahydro-2H-pyran-4-yl)-9H- imidazole-2- purine carbaldehyde 21g2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Reference example 3 2.22 403(tetrahydro-2H-pyran-4-yl)-8-(2,2,2- 2c and 3,3,3-trifluoroethyl)-9H-purine trifluoropropanal 21h8-(1H-pyrazol-3-yl)-2-(pyrazolo[1,5- Reference example 3 1.83 387a]pyridin-3-yl)-9-(tetrahydro-2H- 2c and 1H-pyrazole-pyran-4-yl)-9H-purine 3-carbaldehyde 21i 8-(1-methyl-1H-pyrrol-2-yl)-2-Reference example 3 2.33 400 (pyrazolo[1,5-a]pyridin-3-yl)-9- 2c and1-methyl-1H- (tetrahydro-2H-pyran-4-yl)-9H- pyrrole-2- purinecarbaldehyde 21j 2-(2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Reference example3 2.43 404 (tetrahydro-2H-pyran-4-yl)-9H- 2c and thiazole-2-purin-8-yl)thiazole carbaldehyde 21k 2-(pyrazolo[1,5-a]pyridin-3-yl)-9-Reference example 3 2.32 403 (tetrahydro-2H-pyran-4-yl)-8- 2c andthiophene-2- (thiophen-2-yl)-9H-purine carbaldehyde 21l(S)-3-(9-(1-acetylpiperidin-3-yl)-8- Reference example 3 1.8 465(pyrimidin-5-yl)-9H-purin-2- 2 and pyrimidine-5-yl)pyrazolo[1,5-a]pyridine-5- carbaldehyde carbonitrile 21m(S)-tert-butyl 3-(2-methyl-5- Reference example 3 2.60 433(pyrazolo[1,5-a]pyridin-3-yl)-3H- 2d and imidazo[4,5-b]pyridin-3-acetaldehydee yl)piperidine-1-carboxylate

Example 223-[8-(Ethylamino)-9-tetrahydro-2H-pyran-4-yl-9H-purin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile

To a suspension of the compound obtained in example 1 section d (100 mg,0.30 mmol) in CH₂C₂ (2 mL), ethyl isothiocyanate (0.042 mL, 0.48 mmol),EDC.HCl (171 mg, 0.89 mmol) and DIPEA (0.25 mL, 1.49 mmol) were added.The reaction mixture was heated in a CEM Explorer microwave oven at 80°C. and 150 W for 30 min. Then, it was evaporated to dryness. The crudeproduct thus obtained was chromatographed over silica gel usingMeOH/EtOAc mixtures of increasing polarity as eluent, to afford 42 mg ofthe desired compound (36% yield).

LC-MS (method 1): t_(R)=15.64 min; m/z=389 (MH⁺).

Following a similar procedure to that described in example 22, but usingthe corresponding starting material, the following compound wasobtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 22a3-(8-(pyridin-3-ylamino)-9- Example 1 section 1 16.20 438(tetrahydro-2H-pyran-4-yl)-9H- d, pyridine-3-purin-2-yl)pyrazolo[1,5-a]pyridine-5- isothiocyanate carbonitrile 22b3-(8-(ethylamino)-9-(8- Reference example 1 17.07 455fluorochroman-4-yl)-9H-purin-2- 2e and ethylyl)pyrazolo[1,5-a]pyridine-5- isothiocyanate carbonitrile 22c3-(9-(8-fluorochroman-4-yl)-8- Reference example 1 17.22 504(pyridin-3-ylamino)-9H-purin-2- 2e and pyridine-3-yl)pyrazolo[1,5-a]pyridine-5- isothiocyanate carbonitrile

Example 238-Cyclopentyl-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purine

To a solution of reference example 2c (0.05 g, 0.16 mmol) in DMF (1 mL),cyclopentanecarbaldehyde (0.018 mL, 0.17 mmol) and sodium bisulfite(0.030 g, 0.29 mmol) were added. The reaction mixture was stirred at130° C for 6 h. The solvent was concentrated off and the crude residuewas cromatographed on a silica gel flash system (ISCO Companion) usingCH₂Cl₂/MeOH mixtures of increasing polarity as eluent to afford 37 mg ofthe desired product (60% yield).

LC-MS (method 3): t_(R)=2.40 min; m/z=339 (MH⁺).

Following a similar procedure to that described in example 23, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 23a(S)-3-(9-(1-acetylpiperidin-3-yl)-8- Reference example 2 5 2.42 415ethyl-9H-purin-2-yl)pyrazolo[1,5- and propionaldehydea]pyridine-5-carbonitrile 23b (S)-3-(9-(1-acetylpiperidin-3-yl)-8-Reference example 2 5 2.57 429 isopropyl-9H-purin-2- andisobutyraldehyde yl)pyrazolo[1,5-a]pyridine-5- carbonitrile 23c(S)-3-(9-(1-acetylpiperidin-3-yl)-8- Reference example 2 3 1.78 401methyl-9H-purin-2-yl)pyrazolo[1,5- and acetaldehydea]pyridine-5-carbonitrile 23d 8-cyclopropyl-2-(pyrazolo[1,5- Referenceexample 2c 3 2.05 361 a]pyridin-3-yl)-9-(tetrahydro-2H- andpyran-4-yl)-9H-purine cyclopropanecarbaldehyde

Example 24(S)-3-(1-Acetylpiperidin-3-yl)-1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

To a solution of example 6g (250 mg, 0.65 mmol) in pyridine (10 mL),acetyl chloride (0.92 mL, 1.3 mmol) was added. The reaction mixture wasstirred at room temperature for 5 h. The solvent was concentrated offand the crude residue was cromatographed on a silica gel flash system(SP1 Biotage) using EtOAc/MeOH mixtures of increasing polarity as eluentto afford 196 mg of the desired product (78% yield).

LC-MS (method 4): t_(R)=1.66 min; m/z=391 (MH⁺).

Following a similar procedure to that described in example 24, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Name Starting Material method (min) (MH⁺) 24a(S)-1-methyl-3-(1-pivaloylpiperidin- Example 6g and 4 2.10 4333-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)- pivaloyl chloride1H-imidazo[4,5-b]pyridin-2(3H)-one 24b(S)-3-(1-(4-fluorobenzoyl)piperidin- Example 6g and 4- 4 2.11 4723-yl)-1-methyl-5-(pyrazolo[1,5- fluorobenzoyl chloridea]pyridin-3-yl)-1H-imidazo[4,5- b]pyridin-2(3H)-one 24c(S)-1-methyl-3-(1- Example 6g and 4 1.79 405 propionylpiperidin-3-yl)-5-propionyl chloride (pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

Example 25(S)-1-(3-(1-Methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine--carbonyl)cyclopropanecarbonitrile

To a solution of 1-cyano-1-cyclopropanecarboxylic acid (65 mg. 0.58mmol), in DMF (7 mL), DIEA (0.31 mL, 1.7 mmol), example 6g (248 mg, 0.64mmol) and HBTU (266 mg, 0.70 mmol) were added. The reaction mixture wasstirred at room temperature overnight. The solvent was concentrated offand the crude residue was cromatographed on a silica gel flash system(SP1 Storage) using EtOAc/MeOH mixtures of increasing polarity as eluentto afford the desired with quantitative yield.

LC-MS (method 4): t_(R)=1.92 min; m/z=442 (MH⁺).

Following a similar procedure to that described in example 25, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Name Starting Materials method (min) (MH⁺) 25a9-(1-isobutyrylpiperidin-4-yl)-2- Example 6d and 4 1.59 406(pyrazolo[1,5-a]pyridin-3-yl)-7H- isobutyric acid purin-8(9H)-one 25b9-(1-(2- Example 6d and 2- 4 1.34 421 (dimethylamino)acetyl)piperidin-4-(dimethylamino)acetic yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)- acid7H-purin-8(9H)-one

Example 26 (S)-Methyl3-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)piperidine-1-carboxylate

To a solution of example 6 (200 mg, 0.26 mmol) in DMF (2.6 mL), methylchloroformate (27 mg, 0.28 mmol) and DIPEA (0.068 mL, 0.39 mmol) wereadded. The reaction mixture was stirred at room temperature overnight.The reaction mixture was evaporated under reduced pressure, dissolved inCH₂Cl₂, and washed thrice with saturated NaHCO₃ aqueous solution. Thecombined organic phases were dried over MgSO₄ and concentrated todryness. The crude residue was cromatographed on a silica gel flashsystem (ISCO Combiflash) using CH₂Cl₂/MeOH mixtures of increasingpolarity as eluent to afford 36 mg of the desired product (32% yield).

LC-MS (method 5): t_(R)=2.37 min; m/z=419 (MH⁺).

Following a similar procedure to that described in example 26, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Name Starting Materials method (min) (MH⁺) 26a(S)-ethyl 3-(2-(5-cyanopyrazolo[1,5- Example 6 and ethyl 5 2.53 433a]pyridin-3-yl)-8-oxo-7H-purin- chloroformate9(8H)-yl)piperidine-1-carboxylate 26b (S)-isobutyl 3-(2-(5- Example 6and 5 2.82 461 cyanopyrazolo[1,5-a]pyridin-3-yl)-8- isobutylchloroformate oxo-7H-purin-9(8H)-yl)piperidine-1- carboxylate 26c(S)-3-(2-(5-cyanopyrazolo[1,5- Example 6 and 5 2.33 446a]pyridin-3-yl)-8-oxo-7H-purin- isopropyl isocyanate9(8H)-yl)-N-isopropylpiperidine-1- carboxamide 26d(S)-N-tert-butyl-3-(2-(5- Example 6 and tert- 5 2.52 460°cyanopyrazolo[1,5-a]pyridin-3-yl)-8- butyl isocyanateoxo-7H-purin-9(8H)-yl)piperidine-1- carboxamide 26e (S)-ethyl 9-(1-(2-Example 7f and ethyl 5 2.62 475 cyanoacetyl)piperidin-3-yl)-8-oxo-2-chloroformate (pyrazolo[1,5-a]pyridin-3-yl)-8,9-dihydro-7H-purine-7-carboxylate 26f (S)-3-(3-(7-acetyl-8-oxo-2- Example7f and acetyl 5 2.60 445 (pyrazolo[1,5-a]pyridin-3-yl)-7H- chloridepurin-9(8H)-yl)piperidin-1-yl)-3- oxopropanenitrile 26g(S)-9-(1-acetylpiperidin-3-yl)-7- Example 6u and acetyl 3 1.80 392methyl-2-(pyrazolo[1,5-a]pyridin-3- chloride yl)-7H-purin-8(9H)-one 26h(S)-N-isopropyl-3-(1-methyl-2-oxo- Example 7p and 4 1.85 4345-(pyrazolo[1,5-a]pyridin-3-yl)-1H- isopropyl isocyanateimidazo[4,5-b]pyridin-3(2H)- yl)piperidine-1-carboxamide 26i(S)-3-(3-(1-acetyl-2-oxo-5- Example 7p and acetyl 4 2.01 444(pyrazolo[1,5-a]pyridin-3-yl)-1H- chloride imidazo[4,5-b]pyridin-3(2H)-yl)piperidin-1-yl)-3- oxopropanenitrile 26j (S)-ethyl 3-(1-(2- Example7p and ethyl 4 1.97 474 cyanoacetyl)piperidin-3-yl)-2-oxo-5-chloroformate (pyrazolo[1,5-a]pyridin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine- 1-carboxylate

Example 27(S)-3-(9-(1-(1-Cyanocyclopropanecarbonyl)piperidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Following a similar procedure to that described in example 25, but usingHATU instead of HBTU, and example 6 instead of example 6g, the desiredcompound was obtained (30% yield).

LC-MS (method 3): t_(R)=1.87 min; m/z=454 (MH⁺).

Following a similar procedure to that described in example 27, but usingthe corresponding starting materials, the following compound wasobtained:

HPLC tR m/z Example Name Starting Materials method (min) (MH+) 27a(S)-3-(9-(1-(1- Example 6 and 1- 3 1.7 455hydroxycyclopropanecarbonyl)piperidin- hydroxycyclopropanecarboxylic3-yl)-8-oxo-8,9-dihydro-7H- acid purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Example 28

(R)-3-(9-(1-Hydroxypropan-2-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of example 14 (60 mg, 0.17 mmol) in THF (10 mL) at 0° C.,1 M THF borane complex solution in THF (0.69 mL, 0.69 mmol) was added.The reaction mixture was stirred at room temperature overnight, quenchedwith MeOH (10 mL) and the reaction mixture was evaporated under reducedpressure. The crude residue was cromatographed on a silica gel flashsystem (ISCO Combiflash) using CH₂Cl₂/MeOH mixtures of increasingpolarity as eluent to afford 4 mg of the desired product (7% yield).

LC-MS (method 3): t_(R)=2.02 min; m/z=336 (MH⁺).

Example 29(S)-3-(3-(2-(5-Methylpyrazolo[1,5-a]pyridin-3-yl)-9H-purin-9-yl)piperidin-1-yl)-3-oxopropanenitrilea) (S)-tert-Butyl3-(2-(5-methylpyrazolo[1,5-a]pyridin-3yl)-9H-purin-9-yl)piperidine-1-carboxylate

Following a similar procedure to that described in example 18, but usingreference example 2a instead of the compound obtained in example 1section d, the desired compound was obtained (10% yield).

LC-MS (method 3): t_(R)=2.53 min; m/z=434 (MH⁺).

b)(S)-2-(5-Methylpyrazolo[1,5-a]pyridin-3-yl)-9-(piperidin-3-yl)-9H-purinehydrochloride

Following a similar procedure to that described in example 6, but usingthe compound obtained in the previous section, the desired compound wasobtained (quantitative yield).

LC-MS (method 3): t_(R)=1.7 min; m/z=334 (MH⁺).

c) Title Compound

Following a similar procedure to that described in example 7, but usingthe compound obtained in the previous section, the desired compound wasobtained (57% yield).

LC-MS (method 3): t_(R)=1.78 min; m/z=401 (MH⁺).

Example 301-(4-(2-Pyrazolo[1,5-a]pyridin-3-yl)-9H-purin-9yl)piperidin-1-yl)ethanonea) 9-(Piperidin-4-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9H-purinehydrochloride

Following a similar procedure to that described in example 29 section aand b, but using the compound obtained in reference example 2b insteadof reference example 2a, the desired compound was obtained (10% yield).

b) Title Compound

Following a similar procedure to that described in example 24, but usingthe compound obtained in the previous section, the desired compound wasobtained (quantitative yield).

LC-MS (method 4): t_(R)=1.35 min; m/z=362 (MH⁺).

Example 31(S)-(9-(1-(2-Cyanoacetyl)piperidin-3-yl)-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-8,9-dihydro-7H-purin-7-yl)methylacetate a) (S)-tert-Butyl3-(7-(acetoxymethyl)-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1-carboxylate

Following a similar procedure to that described in example 4, but usingthe compound obtained in example 3b instead of example 1 and bromomethylacetate instead of methyl iodide, the desired compound was obtained (83%yield).

LC-MS (method 3): t_(R)=2.72 min; m/z=508 (MH⁺).

b)(S)-(8-Oxo-9-(piperidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-8,9-dihydro-7H-purin-7-yl)methylacetate hydrochloride

Following a similar procedure to that described in example 6, but usingthe compound obtained in the previous section, the desired compound wasobtained (quantitative yield).

LC-MS (method 3): t_(R)=1.80 min; m/z=408 (MH⁺).

c) Title Compound

Following a similar procedure to that described in example 7, but usingthe compound obtained in the previous section, the desired compound wasobtained (36% yield).

LC-MS (method 3): t_(R)=1.82 min; m/z=475 (MH⁺). p Following a similarprocedure to that described in example 31, but using the correspondingstarting materials, the following compound was obtained:

HPLC tR m/z Example Name Starting Materials method (min) (MH+) 31a(S)-(3-(1-(2-cyanoacetyl)piperidin- Example 7p 4 1.84 4743-yl)-2-oxo-5-(pyrazolo[1,5- a]pyridin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)methyl acetate

Example 32(R)-3-(9-(1-Hydroxypropan-2-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a solution of example 28 (20 mg, 0.06 mmol) in AcN (2 mL) and DMF(0.5 mL) silver (I) oxide (23 mg, 0.12 mmol) and methyl iodide (0.005mL, 0.09 mmol) were added. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was filtered through a plugof Celite® and the solvent was evaporated under reduced pressure. Thecrude residue was cromatographed on a silica gel flash system (ISCOCombiflash) using CH₂Cl₂/MeOH mixtures of increasing polarity as eluentto afford 6 mg of the desired product (29% yield).

LC-MS (method 3): t_(R)=1.75 min; m/z=350 (MH⁺).

Example 332-(Pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-8-amine

To a solution of reference example 2c (144 mg, 0.46 mmol) in EtOH (4mL), cyanogen bromide (147 mg, 1.39 mmol) was added. The reactionmixture was stirred at 70° C. overnight. The reaction mixture wasevaporated under reduced pressure dissolved in EtOAc, and washed thricewith saturated NaHCO₃ aqueous solution. The combined organic phases weredried over MgSO₄ and concentrated to dryness. The reaction crude wasused in next step without further purification.

LC-MS (Method 3): t_(R)=1.53 min; m/z=335 (MH⁺)

Example 341-(2-(Pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-8-yl)pyrrolidin-2-one

To a suspension of example 33 (25 mg, 0.075 mmol) in DMF (1.5 mL), DIPEA(0.04 mL, 0.22 mmol) and 4-bromobutyryl chloride (0.01 mL, 0.082 mmol)ware added. The reaction mixture was stirred at room temperatureovernight. The solvent was evaporated to dryness and 1.7 mg of the titlecompound were obtained (yield 6%) after HPLC preparative purification.

LC-MS (method 3): t_(R)=1.82 min; m/z=404 (MH⁺)

Following a similar procedure to that described in example 34, but usingin each case the corresponding starting materials, the followingcompounds were obtained:

HPLC t_(R) m/z Example Name Starting Materials method (min) (MH⁺) 34aN-(2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Example 33 and 3 1.97 406(tetrahydro-2H-pyran-4-yl)-9H- isobutyryl chloridepurin-8-yl)isobutyramide 34b N-(2-(pyrazolo[1,5-a]pyridin-3-yl)-9-Example 33 and 3 1.77 392 (tetrahydro-2H-pyran-4-yl)-9H- propionylchloride purin-8-yl)propionamide 34cN-(2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Example 33 and acetyl 3 1.60 378(tetrahydro-2H-pyran-4-yl)-9H- chloride purin-8-yl)acetamide

Example 353-(9-(trans-4-Hydroxycyclohexyl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrilea)3-(9-(trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

To a suspension of example 1a (584 mg, 1.55 mmol) in DMF (15 mL),imidazole (265 mg, 3.89 mmol) and tert-butylchlorodimethylsilane (281mg, 1.86 mmol) were added. The reaction mixture was stirred at roomtemperature overnight. The solvent was evaporated to dryness, dissolvedin CH₂Cl₂ and washed thrice with water. The combined organic phases weredried over MgSO₄ and concentrated to dryness. The reaction crude wasused in next step without further purification

LC-MS (method 3): t_(R)=3.38 min; m/z=490 (MH⁺)

b)3-(9-(trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile

Following a similar procedure to that described in example 5, but usingthe compound obtained in the previous section, the desired compound wasobtained (72% yield).

LC-MS (method 2): t_(R)=3.67 min; m/z=504 (MH⁺).

c) Title Compound

To a suspension of the compound obtained in the previous section (246mg, 0.488 mmol) in AcN (10 mL), at 0° C., 1 M TBAF solution in THF (0.73mL, 0.73 mmol) was added. The reaction mixture was stirred at roomtemperature overnight. The solvent was evaporated to dryness, dissolvedin EtOAc and washed thrice with water. The combined organic phases weredried over MgSO4 and concentrated to dryness. The crude residue wascromatographed on a silica gel flash system (ISCO Combiflash) usingCH₂Cl₂/MeOH mixtures of increasing polarity as eluent to afford 77 mg ofthe desired product (40% yield).

LC-MS (method 3): t_(R)=1.82 min; m/z=390 (MH⁺).

Example 362-(2-(5-Cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-(2,2,2-trifluoroethyl)acetamidea)2-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)aceticacid

Following a similar procedure to that described in example 14, but usingthe compound obtained in example 1n instead of example 1a the desiredcompound was obtained

LC-MS (method 3): t_(R)=1.05 min; m/z=336 (MH⁺).

b) Title Compound

Following a similar procedure to that described in example 15, but usingthe compound obtained in the previous section and2,2,2-trifluoroethylamine, the desired compound was obtained.

LC-MS (method 3): t_(R)=1.065 min; m/z=417 (MH⁺).

Following a similar procedure to that described in example 36, but usingthe corresponding starting materials, the following compound wasobtained:

Starting HPLC tR m/z Example Name Materials method (min) (MH+) 36a2-(2-(5- N- 3 1.40 363 cyanopyrazolo- ethylamine [1,5-a]pyridin-3-yl)-8-oxo-7H-purin- 9(8H)-yl)-N- ethylacetamide

Example 372-(Imidazo[1,2-a]pyridin-3-yl)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-onea) 2-Chloro-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-4,5-diamine

Following a similar procedure to that described in example 1 section d,but using the compound obtained in example 1 section a instead of thecompound obtained in example 1 section c the desired compound wasobtained (quantitative yield).

LC-MS (method 1): t_(R)=6.73 min; m/z=229 (MH⁺).

b) 2-Chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one

Following a similar procedure to that described in example 1 section e,but using the compound obtained in the previous section instead of thecompound obtained in example 1 section d, the desired compound wasobtained (83% yield).

LC-MS (method 1): t_(R)=7.16 min; m/z=254 (MH⁺).

c) 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one

Following a similar procedure to that described in example 5, but usingthe compound obtained in the previous section instead of the compoundobtained in example 3b, the desired compound was obtained (58% yield).

LC-MS (method 1): t_(R)=7.51 min; m/z=288 (MH⁺).

d) Title Compound

To a suspension of the compound obtained the previous section (30 mg,0.11 mmol) in EtOH (0.5 mL) and dioxane (1 mL), imidazol[1,2-a]pyridine(16 mg, 0.13 mmol), triphenylphosphine (5.8 mg, 0.02 mmol), potassiumcarbonate (3.1 mg, 0.22 mmol) and palladium (II) acetate (2.5 mg, 0.01mmol) were added. The reaction mixture was heated in a CEM Explorermicrowave oven at 110° C. for 10 min and a 90° C. for 3 h. The reactionmixture was filtered through a plug of Celite® and the solvent wasconcentrated off. A sample was purified by preparative HPLC.

LC-MS (method 4): t_(R)=1.55 min; m/z=351 (MH⁺).

Example 38 Inhibition of JAK3 Activity

The inhibition of JAK3 kinase activity was determined in 384-well assaymicroplates using the Z′-Lyte® Kinase Assay kit-Tyr 6 Peptide kit,supplied by Invitrogan (Ref: PV4122), following the manufacturer'sinstructions. In a final volume of 10 μL per well, 2.5 μL of the productto be tested dissolved in 4% DMSO (final concentration of the product tobe tested, 0.1-10000 nM) was incubated with 0.3 μg/mL of the catalyticdomain of human JAK3 (amino acid sequence 281-1124), 2 μM of thesubstrate peptide Z′-Lyte® Tyr 6 and 4 μM of ATP; all components weredissolved in 50 mM pH 7.5 Hepes buffer, 10 mM Magnesium chloride (II), 1mM EGTA and 0.01% Brij® 35. The reaction was started by the addition ofsaid 4 μM ATP; after incubation for 1 hour at 25° C., 5 μL of A Z′-Lyte®Tyr 6 development reagent was added and the mixture was incubated for 1hour at 25° C. Phosphorylation was then quantified in each well using aSafire2® fluorescence microplate reader from Tecan.

The compounds 1 to 1b, 1d to 1j, 1n to 1p, 1s, 2, 2e, 3 to 3e, 3h to 3i,4, 4b to 5i, 5s, 6 to 6b, 6d to 6f, 6x, 7 to 7d, 7f to 16a, and 16c to17a, 17c to 19, 20 to 29, 31 to 37 showed more than 50% inhibition ofJAK3 activity at 1 μin this assay.

Example 39 Inhibition of JAK2 Activity

The inhibition of JAK2 kinase activity was determined in 384-well assaymicroplates using the Z′-Lyte® Kinase Assay kit-Tyr 6 Peptide kit,supplied by Invitrogen (Ref: PV4122), following the manufacturer'sinstructions. In a final volume of 10 μL per well, 2.5 μL of the productto be tested dissolved in 4% DMSO (final concentration of the product tobe tested, 0.1-10000 nM) was incubated with 0.5 μg/well of the catalyticdomain of human JAK2, 2 μM of the substrate peptide Z′-Lyte® Tyr 6 and16 μM of ATP; all components were dissolved in 50 mM pH 7.5 Hepesbuffer, 10 mM Magnesium chloride (II), 1 mM EGTA and 0.01% Brij® 35. Thereaction was started by the addition of said 16 μM ATP; after incubationfor 1 hour at 25° C., 5 μL of A Z′-Lyte® Tyr 6 development reagent wasadded and the mixture was incubated for 1 hour at 25°C. Phosphorylationwas then quantified in each well using a Safire2® fluorescencemicroplate reader from Tecan.

The compounds 1 to 1b, 1e to 1g, 1n to 1p, 1s, 2, 2e, 3, 3b, 3d, 3e, 4,4c, 5, 5a, 5b, 5e, 5f, 5h, 5i, 5s, 7 to 7c, 7f to 7n, 7p, 7r to 7u, 8 to8c, 8d, 8f to 8h, 9a, 9b, 9c, 9f, 9g, 9i to k, 9m to 9s, 10a, 10b, 10e,10h, 10i, 10k, 10l, 10m, 10n, 13b to 13k, 15 to 15b, 15f, 15h, 15i, 15k,16, 16a, 16d to 16f, 17 to 17c, 18a, 18b, 18d to 18i, 19, 20, 21a to21d, 21g to 21i, 21k, 22 to 23, 23d, 24, 24a, 24b, 24c, 25, 26, 26a,26c, 26d, 26e, 26f, 26g, 27, 27a, 29, 31, 33, 34, 34b, and 35 to 36ashowed more than 50% inhibition of JAK2 activity at 1 μM in this assay.

Example 40 Determination of Clearance in Human Liver Microsomes

A single concentration (1 μM in pH7.4 buffer) of a compound to be testedwas incubated with human liver microsomes for 0, 10, 30 and 60 minutesat 37° C. (0.4 mg protein/mL). The degree of hepatic metabolism wasmeasured by LC-MS/MS as the decrease in the peak area of the parentcompound and expressed as the intrinsic clearance.

Several compounds of the invention were tested in this assay.

Example 41 Cytotoxicity in Hep G2 Cells Assay

Alamar blue (A) was used to evaluate the possible toxicity of a compoundto be tested on Human hepatocyte carcinoma cells (HepG2). The cells(20000 cells/well) were cultured in 96-well plates in the presence ofthe compound at different concentrations (1 to 20 μM) containing 0.2%DMSO for 72 h at 37° C. After addition of AB, fluorescence was measured.EC₅₀ value, defined as the concentration of the compound that results ina decrease in AB fluorescence equivalent to 50% of the control, wascalculated.

Several compounds of the invention were tested in this assay.

1-51. (canceled)
 52. A method of treating a disease mediated by JAKs ina subject in need thereof which comprises administering to said subjectan amount of a compound of formula I or II or a pharmaceuticallyacceptable salt thereof effective to treat said disease

wherein A is carbon and B is nitrogen, or A is nitrogen and B is carbon;W is CH or N; R₁ and R₂ independently are hydrogen, C₁₋₄alkyl,haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,halogen, —CN, —OR₈ or —SR₈; R₃ is C₁₋₄alkyl, R₉—C₁₋₄alkyl, Cy₁ orCy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionally substituted with oneor more R₁₀; R₄ is hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, R₁₂R₇N—C₀₋₄alkyl,R₁₃CONR₇—C₀₋₄alkyl, R₁₃R₇NCO—C₀₋₄alkyl, R₁₂R₇NCONR₇—C₀₋₄alkyl,R₁₃CO₂NR₇—C₀₋₄alkyl, R₁₃SO₂NR₇—C₀₋₄alkyl, —OR₁₂ or Cy₂-C₀₋₄alkyl;wherein Cy₂ is optionally substituted with one or more R₁₁; R₅ ishydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC1-4alkyl, halogen, —CN, —OR₁₂, —NR₇R₁₂, orCy₂-C₀₋₄alkyl, wherein Cy₂ is optionally substituted with one or moreR₁₁; R₆ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,R₁₂R₇N—C₁₋₄alkyl, R₁₆CO—C₀₋₄alkyl, R₁₆CO₂—C₀₋₄alkyl, R₁₆CO—O—C₁₋₄alkyl,cyanoC₁₋₄alkyl, Cy₁ or Cy₂-C₁₋₄alkyl, wherein Cy₁ and Cy₂ are optionallysubstituted with one or more R₁₁; R₇ is hydrogen or C₁₋₄alkyl; R₈ ishydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, orC₁₋₄alkoxyC₁₋₄alkyl; R₉ is halogen, —CN, —CONR₇R₁₂, —COR₁₃, —CO₂R₁₂,—OR₁₂, —OCONR₇R₁₂, —SO₂R₁₃, —SO₂NR₇R₁₂, —NR₇R₁₂, —NR₇COR₁₂,—NR₇CONR₇R₁₂, —NR₇CO₂R₁₃ or —NR₇SO₂R₁₃; R₁₀ is C₁₋₄alkyl orR₉—C₀₋₄alkyl; R₁₁ is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, halogen, —CN, —CONR₇R₁₄, —COR₁₄,—CO₂R₁₅, —OR₁₄, —OCONR₇R₁₄, —SO₂R₁₅, —SO₂NR₇R₁₄, —NR₇R₁₄, —NR₇COR₁₄,—NR₇CONR₇R₁₄, —NR₇CO₂R₁₅ or —NR₇SO₂R₁₅; R₁₂ is hydrogen or R₁₃; R₁₃ isC₁₋₅alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, Cy₂-C₀₋₄alkyl, or R₁₄R₇N—C₁₋₄alkyl; wherein Cy₂ isoptionally substituted with one or more R₁₁; R₁₄ is hydrogen or R₁₅; R₁₅is C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxyC₁₋₄alkyl orcyanoC₁₋₄alkyl; R₁₆ is C_(1-4-l alkyl, haloC) ₁₋₄alkyl,C_(1-4-l alkoxyC) ₁₋₄alkyl or cyanoC₁₋₄alkyl; Cy₁ is a 3- to 7-memberedmonocyclic or 6- to 11-membered bicyclic ring, which is saturated,partially unsaturated or aromatic, and which is carbocyclic orheterocyclic containing from 1 to 4 heteroatoms independently selectedfrom N, S and O, wherein said ring is bonded to the rest of the moleculethrough any available C atom, and wherein one or more C or S ring atomsare optionally oxidized forming CO, SO or SO₂; and CY₂ is a 3- to7-membered monocyclic or 6- or 11-membered bicyclic ring, which issaturated, partially unsaturated or aromatic, and which is carbocyclicor heterocyclic containing from 1 to 4 heteroatoms independentlyselected from N, S and O, wherein said ring is bonded to the rest of themolecule through any available C or N atom, and wherein one or more C orS ring atoms are optionally oxidized forming CO, SO or SO₂.
 53. Themethod according to claim 52, wherein the disease is selected from thegroup consisting of transplant rejection, immune, autoimmune orinflammatory diseases, neurodegenerative diseases, and proliferativedisorders.
 54. The method according to claim 52, wherein the disease isselected from the group consisting of transplant rejection, rheumatoidarthritis, psoriatic arthritis, psoriasis, type I diabetes,complications from diabetes, multiple sclerosis, systemic lupuserythematosus, atopic dermatitis, mast cell-mediated allergic reactions,inflammatory or autoimmune ocular diseases, leukemias, lymphomas, andthromboembolic and allergic complications associated with leukemias andlymphomas.
 55. (canceled)